Folic acid, single added active ingredient by mouth × Hemoglobin increase in confirmed folate-deficient megaloblastic anemia

Required evidence, verification status and materials actually read
Item	AVerification status	BReading scope	CReview item	DCurrent findings	EWhy unverified	FRequired materials and conditions	GFurther research
1	Met	Full text not readStored summary read	N01 · Boundary of the distinct claimWhich population with deficiency, oral folic acid comparison and Hb outcome does this table address?Required	The original claim is an increase in Hb in confirmed folate-deficient megaloblastic anemia. It was fixed as one comparison with oral folic acid as the sole addition under the same background care, and subclaims is an empty list.	The original claim was linked to the inclusion and exclusion boundaries. This does not establish efficacy or constitute a new verdict.	The current original claim and specifications for laboratory confirmation, B12 exclusion, ingredient, route, background care and control, Hb and time point	Future comparisons should first specify this population and the Hb effect of interest, and report other etiologies and endpoints as separate questions.
2	Partly verified	Full text not readStored summary read	N02 · Laboratory confirmation and B12 exclusionHow were isolated folate deficiency and megaloblastic anemia confirmed, and how was B12 deficiency excluded?Required	The question requires laboratory-confirmed isolated deficiency and exclusion of B12 deficiency, but the diagnostic cutoffs in an eligible comparison remain unverified. Golding's tests, marrow findings and B12 monitoring provide context; they are not themselves between-group results for this population. S01 S08 S09	The population specified by the question and some human test records are verified, but the confirmation criteria and separately identified population in an eligible comparison have not been verified.	The original diagnostic framework, serum/RBC folate, Hb/MCV, marrow, B12 and functional markers, and exclusion criteria	Record the diagnostic and B12-exclusion procedures, and separate results for the confirmed isolated-deficiency population from those for other deficiency strata.
3	Met	Full text not readStored summary read	N03 · Other etiologies and special populationsWere groups with other etiologies, including pregnancy, mixed deficiencies, drugs, alcohol and malabsorption, distinguished?Required	Material on cancer/olaparib, alcohol/liver disease/bleeding, tropical sprue, pregnancy and combinations with B12 was not pooled with direct comparisons in adults with isolated deficiency. Pediatric cases and mixed B12/iron deficiency, renal disease, hemolysis, aplasia and inflammatory causes also remain outside that boundary. S02 S03 S04 S07 S13	The population differences and reasons for exclusion stated in the original text were preserved. Extension to other populations has not been verified.	Information on diagnosis by etiology, coexisting deficiencies, pregnancy/lactation, age, liver and kidney status, drugs and malabsorption	Future studies should distinguish mixed deficiencies and special etiologies in advance and present direct comparisons separately for each population stratum.
4	Partly verified	Full text not readStored summary read	N04 · Chemical form and product identityWere folic acid and the actual dosage form, manufacturer and product in an eligible comparison verified?Required	The chemical form in the question is folic acid, distinguished from folinic acid and 5-MTHF. The salt, dosage form, brand, manufacturer, batch and purity in an eligible comparison remain unverified. The 5 mg oral tablet in S11 was retained only as product context. S11	The chemical form specified by the question and information about an official product are available, but the product in an eligible comparison has not been verified.	Original records of chemical form, salt, sole active ingredient, dosage form, manufacturer, brand, batch and purity	Record the identifiable single-ingredient folic acid product and each group's product, batch, purity and other active ingredients.
5	Unverified	Full text not readStored summary read	N05 · Route, dose and durationWere the dose, dosing frequency, treatment duration and exposure of an eligible oral regimen verified?Required	The dose, dosing frequency and treatment duration in an eligible comparison remain unverified. The 1 mg/day used in the olaparib population and the 5 mg/day for 4 months in the S11 label are not used as verified regimens for this question. S02 S11	The oral route is specified in the question, but the actual dose and duration in an eligible comparison could not be verified.	Original data on route, daily dose, dosing frequency, total exposure, treatment duration and concurrent supplementation for each eligible group	Record actual use, adherence and concurrent supplementation for the sole oral addition, and directly compare justified dose/duration questions.
6	Unverified	Full text not readStored summary read	N06 · Same background care and actual controlWere background treatment apart from folic acid and a control without added folic acid actually compared?Required	The question specifies a control without added folic acid under the same background treatment, but an actual eligible comparison remains unverified. Golding had no concurrent control, and Shammo's controls also underwent olaparib dose reduction. S01 S02	The current related material alone cannot verify a between-group contrast under the same background care in the isolated-deficiency population.	Original records of background treatment, concurrent supplementation, diet, transfusion, rescue treatment and the control without added folic acid for each group	Define the ethically permissible comparison and effect of interest, and report background treatment, rescue treatment and changes by group.
7	Met	Full text not readStored summary read	N07 · Hb measurements and other endpointsIs the primary outcome the between-group change in Hb, distinguished from MCV, reticulocytes, folate and other measures?Required	The primary outcome is the between-group difference in change in blood Hb at a predefined time; an appropriately adjusted difference in final values is separate. MCV, reticulocytes, folate concentrations, fatigue, transfusion and correction rates do not substitute for the primary outcome.	The boundary between the selected endpoint and other endpoints was linked to the original text. An actual Hb effect estimate has not been verified.	Hb definition, change/final values, units, direction of comparison, predefined follow-up time and a list of other endpoints	Define Hb measurement and analysis in advance, and report other markers, symptoms, transfusion and correction rates as separate outcomes.
8	Unverified	Full text not readStored summary read	N08 · Predefined time point and follow-up coordinatesCan the fixed Hb follow-up time in an eligible comparison be distinguished from treatment and observation durations?Required	The fixed Hb follow-up time and the treatment and follow-up durations in an eligible comparison remain unverified. The self-experiment's coordinates—diet resumed on day 586, a nadir near day 588 and return by day 772—are not repurposed as a treatment effect at a fixed time point. S01	The time point in the main question was defined, but the predefined time point in an actual eligible comparison could not be verified.	Original registration/protocol records of the primary Hb time point, measurement schedule, treatment, discontinuation and follow-up duration	Specify treatment exposure and the Hb follow-up schedule, and measure the effects of continuation and discontinuation as separate questions defined in advance.
9	Unverified	Full text not readStored summary read	N09 · Hb testing and measurement conditionsWere Hb measurement and differences in transfusion, bleeding and testing that affect anemia verified?Required	The Hb assay, measurement schedule, transfusion/bleeding by group and assessment procedures in the fixed comparison have not been verified. Recovery in a case involving alcohol, liver disease and bleeding is not used as a comparison with matched measurement conditions. S03	No eligible material is available to link direct Hb values to measurement conditions.	Records of the Hb assay, units, specimen/collection schedule, assessor blinding, transfusion, bleeding and changes by group in an eligible comparison	Standardize testing and specimen schedules, transfusion/bleeding and concurrent treatment, or report the actual differences and how they were handled analytically.
10	Unverified	Full text not readStored summary read	N10 · Eligible comparative designWere the actual comparative design, allocation and baseline balance in the isolated-deficiency population verified?Required	Prospective human observation and a small comparison in a cancer population are verified, but an eligible between-group Hb design in adults with confirmed isolated deficiency and B12 deficiency excluded remains unverified. The original evidence_status records the existence of human data separately from the absence of an eligible comparison. S01 S02	Material with other designs or populations does not substitute for the direct-comparison gate.	Original records of selection, design, allocation/concealment, baseline status, background care and control, and denominators in an eligible comparison	Specify an ethically permissible prospective comparison and the effect of interest, and record selection/allocation and baseline confounding.
11	Partly verified	Full text not readStored summary read	N11 · Golding: design and denominator for 1 participantWere the participant count and the number of analytical replicates in Golding's self-experiment distinguished?Required	Golding is a depletion-and-repletion self-experiment involving 1 participant. The randomized count is 0 and the eligible concurrent-control count is 0; analytical replicates are not participants. The recovery record is not a between-group Hb effect. S01	The design and participant count are verified, but they do not provide the comparison specified by the main question.	Original records of the self-experiment's design, participant/randomized/control counts and repeated tests	In prospective data, report participants, specimens and analytical replicates separately, and specify the limitations of the comparison.
12	Partly verified	Full text not readStored summary read	N12 · Golding: recovery and graphsTo what extent were Golding's Hb recovery timing and graph values read?Required	Normal diet and folate supplementation resumed on study day 586; the Hb, red-cell count and hematocrit nadir was near day 588, and return to initial levels was reported by day 772. Numerical values were not reconstructed from graph heights. S01	The favorable recovery context and time coordinates are preserved, but they are not a controlled treatment effect or a general recovery duration.	The depletion-and-repletion timeline, reported Hb trajectory and extent of reading of the original graph	Observational studies should report Hb trajectories, times of changes and conditions that changed together, and distinguish causal effects from descriptive data.
13	Partly verified	Full text not readStored summary read	N13 · Golding: concurrent diet and B12Were Golding's resumption of normal diet and concurrent B12 use distinguished from the contribution of folic acid?Required	Golding's participant maintained methylcobalamin 1000 µg/day and monitored B12 markers. Normal diet and folate supplementation resumed together, so the before-and-after recovery is not interpreted as an isolated between-group effect of folic acid. S01	Cointervention records are verified, but there is no control from which to estimate the independent contribution of folic acid.	Original records of diet, folate, methylcobalamin, B12 tests and times of changes	Record concurrent nutrients, drugs, diet and the times of changes, and separate the incremental contribution of the ingredient of interest through an appropriate comparison.
14	Not met	Full text not readStored summary read	N14 · Olaparib: directness of the populationIs Shammo's cancer/olaparib population the same as a population with confirmed isolated folate-deficiency anemia?Required	Shammo is a prospective study of patients receiving olaparib for cancer. An eligible between-group Hb result for the stratum with confirmed megaloblastic anemia and B12 deficiency excluded could not be separately verified. S02	The currently verified population and outcomes do not meet the direct criteria of the question about adults with isolated deficiency.	Original data on cancer/drugs, anemia/folate diagnosis, and the stratum with megaloblastic anemia and B12 deficiency excluded	Separate population strata with drug-induced causes from those with isolated deficiency, and report Hb comparisons by stratum.
15	Partly verified	Full text not readStored summary read	N15 · Olaparib: enrollment, allocation and completionWere the 9 enrolled participants, the 2+2 allocated participants and the 12-month completion denominator distinguished?Required	Of 10 people who consented, 9 enrolled, and 4 were allocated as 2 to folic acid versus 2 to no supplementation. There were 5 nonrandomized participants, and the 5 who completed 12 months refer to the entire cohort. The fixed-time Hb analysis denominators by group remain unverified. S02	The overall flow is verified, but Hb analysis denominators by group and the fixed time point have not been verified.	Original flow records for consent, enrollment, randomization, nonrandomization, completion and Hb analysis by group	Report the flow of the entire cohort separately from that of the allocated subgroup, and provide analysis denominators at each Hb time point.
16	Partly verified	Full text not readStored summary read	N16 · Olaparib: dose and rescue criteriaTo which trial do Shammo's 1 mg/day dose and folate/Hb allocation and rescue criteria belong?Required	Shammo used oral folic acid at 1 mg/day. Allocation occurred at folate <7 ng/mL and Hb <12 g/dL, and the protocol specified starting rescue folate at Hb <10 g/dL regardless of allocation. This protocol is not used as universal criteria for confirming deficiency or megaloblastic anemia. S02	Exposure and protocol details for that oncology trial are preserved, but the regimen and analysis of rescue use for the main population remain unverified.	The original trial dose, folate/Hb allocation criteria, rescue policy and actual use by group	Record the ethical rescue policy, actual timing of use and denominators, and specify its impact in the analysis of the effect of interest.
17	Partly verified	Full text not readStored summary read	N17 · Olaparib: change in controlWere Shammo's change from the placebo plan and the actual control without supplementation distinguished?Required	Shammo's initial placebo plan changed to a control without supplementation because of cost. It is a small open-label randomized component within a prospective cohort and is not presented as a randomized double-blind placebo Hb trial. S02 S10	The current retained wording verifies the difference between the planned and actual control, but the full protocol, SAP and amendment history remain unverified.	The original plan, reasons for changes, open-label/blinding status, actual control without supplementation and analysis documents	Transparently report the plan, reasons for changes, actual control, blinding and Hb analysis of interest.
18	Conflicting information	Full text not readStored summary read	N18 · Olaparib: conflicting trial-phase wordingWere the phase IV and phase II/single-arm labels recorded in Shammo's original text preserved without arbitrarily harmonizing them?Required	The retained citation records a discrepancy between the phase IV narrative on PDF p.1/3 and the phase II/single-arm template on p.2. The small randomized component actually linked in the record is retained, and the phase labels were not arbitrarily corrected. S02	This is an explicit conflict in phase/design wording within the same report, not merely a difference between analyses.	The relevant original pages, design wording, corrections or author explanations	Align design labels with the actual allocation component, and record an original explanation or correction as a separate event when available.
19	Partly verified	Full text not readStored summary read	N19 · Olaparib: Hb and background medicationWere Shammo's interpretation of secondary Hb results and olaparib dose reduction kept from being converted into a between-group effect?Required	Shammo's primary question concerns the frequency and timing of folate deficiency, and Hb is secondary. Olaparib dose reduction in controls is asymmetric, and a formal between-group Hb estimate for the fixed population stratum remains unverified. Recovery of deficient folate concentrations and the authors' interpretation are not converted into equivalence. S02	The endpoint hierarchy and changes in background care are preserved, but the direct Hb effect of interest could not be verified.	Secondary Hb results, medication changes by group, formal Hb estimates/variance/time points and the original protocol	Predefine Hb as the outcome of interest, record background medication and rescue treatment, and report adjusted and sensitivity analyses for the comparison of interest.
20	Not met	Full text not readStored summary read	N20 · Alcohol and malabsorption materialHow were Clarke's case and Sheehy's tropical-sprue material preserved?Required	Clarke is a 1-person case involving alcohol, liver disease and bleeding. Detailed transfusion counts, dose and a causal Hb effect remain unverified within the retained scope. Sheehy is a historical dose-titration study in tropical-sprue malabsorption; matching B12 exclusion and an Hb contrast for oral folic acid versus no added folic acid remain unverified. S03 S04	The current populations and designs do not match the comparison of folic acid alone in adults with isolated deficiency. Recovery context and access limitations are retained.	Case etiology, cointerventions/transfusion, administration/control, B12 exclusion, Hb values and the actual extent of access	Report etiology, concurrent treatment, tests and denominators separately, and evaluate them through a comparison appropriate to that population's question.
21	Not met	Full text not readStored summary read	N21 · Folate markers in people without anemiaDoes Obeid's folate-marker study in nonpregnant women provide an Hb treatment result in confirmed anemia?Required	Obeid is an index-level lead identifying a folate-biomarker supplementation study in nonpregnant women. It was not used as a direct Hb effect of treatment for confirmed megaloblastic anemia, and the current n record is empty. S06	The currently verified population/endpoints differ from the Hb comparison in confirmed anemia specified by the main question.	Actual anemia diagnosis, baseline status, Hb outcomes, folate markers and the location of the selection information	Separate baseline anemia and deficiency from outcomes, and provide a direct Hb comparison when the question concerns Hb treatment.
22	Not met	Full text not readStored summary read	N22 · Combined B vitamins in MSCan Nozari's combined B12+folic acid intervention in MS be separated into an effect of folic acid alone?Required	Nozari is a comparison adding B12 and folic acid together in an MS population. It does not provide a between-group Hb result for folic acid as the sole addition in adults with isolated deficiency, and n remains unverified within the index-level access scope. S07	The population and intervention differ from the main question, and the contribution of folic acid alone cannot be isolated.	The MS population, B12/folic acid interventions by group, Hb/anemia/quality-of-life outcomes and a contrast with a sole added ingredient	If the question concerns each ingredient's contribution, design a direct contrast with matched background care and separate outcomes by disease.
23	Not met	Full text not readStored summary read	N23 · Pregnancy review and reused citationWere the pregnancy review and trials from historical record 121 kept from being counted as independent replications of replacement treatment in adults?Required	S13 is the URL/citation of a pregnancy review inherited from the original 121. Pregnancy-prevention results and the historical combined-claim page were not counted as replications of deficiency treatment in nonpregnant people, and the original file was not reopened in this review. S13	The population and prevention/treatment boundary differ, so the criteria for direct treatment replication are not met.	The actual populations and prevention/treatment questions of the review/included trials, and links to original data	Link included trials to unique study families and their actual populations, interventions and outcomes, then separately review only material relevant to the question.
24	Unverified	Full text not readStored summary read	N24 · Between-group effect, variance and intervalWere the direct Hb difference in change, adjusted difference in final values, and SD/SE, CI and P verified?Required	The fixed question's between-group Hb difference in change, adjusted difference in final values, variance, CI, P and analysis n by group remain unverified. The original calculation fields mean_changes, sd_changes, difference, interval and n are preserved as null.	The inputs and estimates needed for a quantitative direct comparison are unavailable, so no interval could be verified for interpretation.	Original tables of Hb values/changes, units, n and SD/SE for each eligible group, the estimation model, CI and P	Provide group-specific outcomes and variance, and the estimate and CI for the effect of interest; explain change/final-value analyses and adjustment variables.
25	Unverified	Full text not readStored summary read	N25 · Analysis population and missing dataWere ITT/PP, completion/analysis denominators, missing data and Hb analysis in the main comparison verified?Required	Eligible analysis and completion denominators by group, ITT/PP and missing-data handling for the main question remain unverified. Shammo's 5 completers at 12 months across the entire cohort were not used as Hb completion n for the two arms. S02 S10	Eligible Hb analysis information is unavailable, and the flow of a related cohort does not substitute for the main analysis.	Flow, Hb measurement/analysis n, ITT/PP, reasons for and handling of missing data, and sensitivity analyses for each eligible group	Define the effect of interest and analysis population in advance, and report how missing Hb data, dropout and rescue treatment were handled by group, together with sensitivity analyses.
26	Unverified	Full text not readStored summary read	N26 · Important difference and extension to clinical outcomesWere the clinical importance of Hb and questions about symptoms, transfusion and survival distinguished?Supplementary; required for claims about importance or extension to event outcomes	A clinically important Hb criterion for the main question remains unverified. Hb concentration is laboratory surrogate endpoint S and is not automatically extended to direct effects on fatigue, transfusion, correction rates or survival.	The magnitude of clinical benefit cannot be determined because importance criteria and direct event outcomes have not been verified.	A justified criterion for an important Hb difference in the relevant population, and direct outcomes for symptoms, transfusion and quality of life/survival	Justify an important Hb difference for the population and context, and measure patient-centered events as separate outcomes.
27	Partly verified	Full text not readStored summary read	N27 · Study families, funding and disclosuresTo what extent were each report's family and funding/product/conflict-of-interest information verified?Supplementary; required for a claim of independence	S02 and S10 are the paper and registration for NCT04024254. S11 is product labeling, and S13 is a reused citation of a historical review. Funding in evidence only refers to a separate evidence_appraisal.json, and citation only records the locations of COI/funding sections, so the actual disclosures are not described as verified in this review. S01 S02 S10 S11 S13	Verified families/roles were linked, but the detailed original values for funding, products and author disclosures are absent from the current stored summaries.	Unique-study/reused-citation relationships and original wording on research funding, product provision and author disclosures	Disclose family relationships, overlapping reports, funding and product roles, and verify independent direct comparisons through actual links.
28	Partly verified	Full text not readStored summary read	N28 · Registration, protocol and hierarchyWere the registry shell and the original protocol/SAP, amendment history and current status distinguished?Required	NCT04024254 is a registry-shell record linked to S02 Methods. Registration timing, amendments and current status were not independently certified in the historical review, and history/results/protocol contents are retained as not accessed. S02 S10	The registration identity was linked, but the endpoints, time points, SAP and cross-check of the full history remain unverified.	The original NCT04024254 registration/history, protocol, SAP, Hb hierarchy/time points and reasons for amendments	Link the Hb outcome, time point and analysis of interest, and actual amendments, to public records and cross-check them against actual reporting.
29	Partly verified	Full text not readStored summary read	N29 · B12 guideline versionWere BSH's replacement notice and the unverified NICE details distinguished?Supplementary; required for diagnostic and safety applications	The retained record states that the BSH page identifies the document dated 2014-06-18 and, in its 2024-11-20 update, announces replacement of B12 guidance by NICE NG239 dated 2024-03-06. Exact NICE B12/MMA cutoffs and treatment instructions could not be extracted. S08 S09	The replacement identity/version notice is preserved, but the original diagnostic details have not been verified.	BSH version/update notices, the identity of NICE NG239 and the actual original diagnostic/treatment recommendations	When updating diagnostic/safety criteria, cross-check the actual original recommendations, version, applicable population and reasons for changes.
30	Met	Full text not readStored summary read	N30 · HTA of folate testingWas the Swiss HTA's evidence on testing utility kept from being transferred into a claim of no effect of folic acid treatment?Required	The Swiss 2023 HTA evaluates the clinical utility of folate testing itself. Gaps in testing evidence were not repurposed as ineffectiveness of replacement treatment or a worldwide absence of treatment research. Only selected narrative sections were read at that time; numerical appendices and cutoffs could not be extracted. S12	The difference between questions and the reading limitations in the current stored material were linked. This does not verify a treatment effect.	The HTA's question about the clinical utility of testing, original sections/pages and distinction from the treatment context	Evaluate patient outcomes and treatment comparisons for a testing strategy separately from direct replacement-treatment effects as distinct research questions.
31	Partly verified	Full text not readStored summary read	N31 · Official treatment context and labeled regimenWere recognized replacement treatment and the dose on the S11 label distinguished from a direct comparative effect?Required	S11 describes single-ingredient oral folic acid tablets and the indication of folate-deficient megaloblastic anemia. The adult regimen of 5 mg/day for 4 months belongs to that product's labeling; it is not the regimen of an eligible trial in this review, a placebo-controlled effect estimate or an individual instruction. S11	The official product's treatment context is a verified retained record, but the quantitative effect in the main comparison remains unverified.	S11 product identity, indication, labeled dose/duration and version, and the identity of an eligible trial	Use labeling as treatment context, and report the actual comparison, exposure and Hb outcomes for the question of interest separately.
32	Met	Full text not readStored summary read	N32 · RE and treatment-ethics boundariesWere the original nonapplication of RE, allowance for prospective observation and prohibition on withholding treatment retained unchanged?Required	The original review acknowledged objective diagnosis, a direct replacement mechanism and prospective human observation. RE was not applied because proof of the historical absence of placebo trials and quantitative evidence of untreated mortality/irreversible harm were not obtained. The allowance for prospective observation is not changed into a requirement for a placebo RCT. S01 S02 S11 S12	The original RE logic and the boundaries for presenting treatment ethics were preserved accurately. RE was not newly adjudicated or established as met.	The original reasons for the RE decision, objective diagnosis/replacement mechanism, prospective observation and the extent of verification of the five gates at that time	First define an ethical comparison appropriate to this question and the effect of interest, then evaluate actual data; do not recommend a no-treatment experiment.
33	Partly verified	Full text not readStored summary read	N33 · B12 masking and neurological riskWas improvement in Hb distinguished from resolution of neurological problems due to B12 deficiency?Supplementary; required for safety boundaries	S11 warns against treating B12 deficiency/undiagnosed anemia with folic acid alone, because folic acid can improve the hematologic findings of B12 deficiency and delay recognition of neurological damage. Hb recovery is not evidence that the B12 problem has been resolved. S11	The label warning is preserved, but the frequency of neurological harm in the selected population and at the selected dose remains unverified.	S11 contraindications and precautions for B12 deficiency/undiagnosed anemia, and actual neurological-harm definitions and exposure/denominator data	Record B12 exclusion and neurological observations, and separately collect actual harm definitions, timing, exposure and denominators.
34	Partly verified	Full text not readStored summary read	N34 · Adverse reactions, drugs and denominatorsWere gastrointestinal and allergic reactions and interactions distinguished from actual event denominators in the eligible population?Supplementary; required for frequency/safety claims	The context of gastrointestinal and allergic adverse reactions and interactions with antiepileptics and methotrexate in the product label was preserved. This is not AE/SAE, discontinuation-count, denominator or incidence data for the main isolated-deficiency population. S05 S11	Warning/reaction context is available, but comparative frequencies and the extent of data collection for the same population and exposure remain unverified.	Original data on AE/SAE, discontinuation, exposure/duration, collection methods, people with events/event counts and concomitant drugs for each eligible group	Report harm definitions, systematic collection, people/event counts, exposure time and denominators by group, and analyze drug interactions in their relevant context.
35	Unverified	Full text not readStored summary read	N35 · Long-term use and special populationsCan safety/efficacy be extended to high doses, long-term use, liver or kidney disease, cancer, malabsorption, pregnancy/lactation and children?Supplementary; required for extension claims	Applicability differs for long-term high doses, liver or kidney disease, malabsorption, a history of cancer, pregnancy/lactation and children. Their efficacy, incidence or safety is not established from the current main question or product labeling. S11	Direct material for each extension has not currently been verified, and the populations also differ from the original question.	Actual exposure/effect by population, dose and duration, rare/long-term harms, and drug/underlying-disease data	For each extension question, separately collect appropriate design, exposure, long-term follow-up and outcomes in vulnerable populations.
36	Met	Full text not readStored summary read	N36 · Current and historical readingWas historical access for the 13 bibliographic records distinguished from reading local summaries in this review?Required	In this review, the Korean text/structure of the current stored summaries and 13 bibliographic records were read. Historical levels such as Golding HTML, parsed Shammo text and official labeling/HTA are retained reports; no clinical full text was read in this review. Report-specific access dates are absent and left empty, while the original review date is separately recorded as 2026-09-15. S01 S02 S03 S04 S05 S06 S07 S08 S09 S10 S11 S12 S13	Actual summary reading was separated from current nonreading and historical access by material type. This does not mean full-text verification was completed.	Material type, URL, historical access_level/flag, dates and original locations for each report, and exact current stored-summary anchors	During any authorized subsequent material check, record original locations, material type, dates, acquisition/reading and access failures separately.
37	Met	Full text not readStored summary read	N37 · Original-verdict and publication boundariesWere the original ?/empty values, axes, safety and publication records distinguished from the new criteria statuses?Required	The original grade is ?, score is null, safety is Caution, and the five axes beyond B/S are null. The existence of human research is distinguished from unverified directly eligible results. The original server_deployed=true, server_write=false and 2026-09-15 publication metadata are historical records; the new table has not been deployed.	The original verdict and scope metadata were preserved, and no new score or efficacy judgment was assigned to criteria statuses.	Original grade/score/axes, calculation, evidence_status, publication/server metadata and the scope of the new table	Separate material/criteria updates from the original clinical verdict and events of public release, preserving the original text before and after changes.
38	Met	Full text not readStored summary read	N38 · Search limitations and links to updatesWhat would actually update the gaps within the retained search scope of 2026-09-15?Required	The original cutoff date is 2026-09-15, and the search was limited, including selected full texts, abstracts and inaccessible material. The retained policy is to append to the history under the same ID/URL when new matching Hb results, original texts/protocols, corrections/retractions, numerical/classification errors or B12 diagnostic/safety changes are actually verified.	The scope of the original gaps was distinguished from update events. This does not mean new material has been verified or the search is complete.	New direct Hb results, actual original texts/protocols, corrections/retractions, and evidence of numerical, classification, diagnostic and safety changes	Subsequent updates should establish material identity, dates, original locations and reading scope, and cross-check the question of interest together with the original results and gaps.

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38 itemsWhat the statuses mean

Assessment scope

Stored-material review date: 2026-10-05
Original evidence cut-off: 2026-09-15
Scope actually checked: Stored Korean and English manuscripts and case-specific criteria and application records. Full papers, supplements, registrations, plans and original data were not read.
What the dates mean: This is the date the stored materials were checked, not the date of an up-to-date clinical literature search.
Population: Nonpregnant, nonlactating adults; laboratory-confirmed isolated folate-deficient megaloblastic anemia; B12 deficiency excluded. Groups with special etiologies are kept separate.
Ingredient, formulation and route: Folic acid · The question is bounded to a single-ingredient oral preparation; the salt, dosage form and brand in an eligible trial remain unverified. · Oral
Dose: Unverified — the dose and dosing frequency in an eligible comparison have not been verified.
Comparator: Placebo, no treatment or usual care with no added folic acid, under the same background treatment. An actual eligible comparison remains unverified.
Measured outcome: Between-group difference in change in blood hemoglobin at a predefined follow-up time; an appropriately adjusted difference in final values is considered separately. Keep g/dL and g/L, and each time point, separate.
Duration: Unverified — the treatment and follow-up durations in an eligible comparison have not been verified.
Questions outside this scope: MCV/reticulocytes/folate/clinical events as Hb substitutes; Golding uncontrolled diet/B12 cointerventions; oncology olaparib etiology and rescue; alcohol/liver/bleeding and tropical-sprue causes; MS multicomponent and pregnancy-prevention review

Evidence and sources

The links below lead to the sources. A link alone does not mean the original source was read or its latest publication status verified.

S01 · Golding 2014: Severe experimental folate deficiency in a human subject

Source

Material type: Before-and-after observation of depletion and repletion in 1 person
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: This is a self-experiment with 1 participant. There is no concurrent control without added folic acid, and the context includes resumption of normal diet, folate and methylcobalamin 1000 µg/day. Resumption on study day 586, the nadir near day 588 and recovery by day 772 describe a trajectory; Hb values or between-group effects were not reconstructed from graphs.
Record level: Before-and-after observation of depletion and repletion in 1 person; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full text of the paper Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S02 · Shammo et al. 2025: A prospective study of serum folate levels in patients with solid tumors treated with olaparib

Source

Material type: Small comparison within a prospective cancer/olaparib cohort
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: Of 10 people who consented and 9 who enrolled, 4 were allocated as 2 to folic acid versus 2 to no supplementation; the 5 who completed 12 months in the entire cohort are not the Hb analysis denominators by group. Oral 1 mg/day, allocation/rescue criteria, abandonment of placebo because of cost and dose reduction of the drug in controls were preserved. Hb is secondary, and a formal Hb effect in the stratum with confirmed isolated deficiency/B12 exclusion remains unverified. The phase IV versus phase II/single-arm wording conflict was also retained.
Record level: Small comparison within a prospective cancer/olaparib cohort; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full text of the paper Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S03 · Clarke and Weston-Smith 2010: Severe folate-deficiency pancytopenia

Source

Material type: Case involving alcohol, liver disease and bleeding in 1 person
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: This provides context on hematologic recovery in a case involving 1 person. Alcohol, liver disease and bleeding coexist, and detailed transfusion counts, folic acid dose and a causal Hb effect remain unverified within the retained access scope. It is not a controlled mean Hb effect in the isolated-deficiency population.
Record level: Case involving alcohol, liver disease and bleeding in 1 person; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full bibliographic/abstract web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.
Full text of the paper Material URL unverified	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. The current record has no direct URL for the relevant full text/protocol. A bibliographic URL is not converted into a full-text download link. This does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S04 · Sheehy et al. 1961: The effect of minute and titrated amounts of folic acid on the megaloblastic anemia of tropical sprue

Source

Material type: Historical dose-titration material in tropical sprue
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: This is a historical dose-titration study in a malabsorption population. The current n is a string representing an empty object, and B12 exclusion, a comparison of oral folic acid against a control without added folic acid, and Hb values for the fixed population remain unverified. Historical failure to access the publisher's original full text is not presented as a failure in this review.
Record level: Historical dose-titration material in tropical sprue; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full bibliographic/abstract web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.
Full text of the paper Material URL unverified	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. The current record has no direct URL for the relevant full text/protocol. A bibliographic URL is not converted into a full-text download link. This does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S05 · NIH ODS Folate health-professional fact sheet

Source

Material type: Limited historical access to official nutrition and safety context
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: ODS is a lead for safety and medication context. The record preserves initial access to body text followed by repeated access failures and states that safety interpretations requiring exact wording were corroborated by S11. No new numerical UL was invented from unverified sections, and this is not Hb treatment-effect data.
Record level: Limited historical access to official nutrition and safety context; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full official web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S06 · Obeid et al. 2017: Folate supplementation in nonpregnant women

Source

Material type: Index-level lead on folate-biomarker supplementation in people without anemia
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: The record states that folate-biomarker supplementation material in nonpregnant women was reviewed at index level. This differs from Hb treatment of confirmed megaloblastic anemia, and current n and direct Hb values remain unverified. It is not upgraded into a review of the quality/effects of the entire original full text.
Record level: Index-level lead on folate-biomarker supplementation in people without anemia; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full text of the paper Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S07 · Nozari et al. 2019: Folic acid and vitamin B12 supplementation in multiple sclerosis

Source

Material type: Index-level lead on combined B12+folic acid in MS
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: This is a comparison adding B12+folic acid together in an MS population. The Hb effect of folic acid as the sole addition in isolated folate deficiency was not separated, and current n remains unverified. Material with a different population and ingredients is not used as direct replication.
Record level: Index-level lead on combined B12+folic acid in MS; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full text of the paper Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S08 · British Society for Haematology: Diagnosis of B12 and Folate Deficiency

Source

Material type: Notice of a historical guideline's version and replacement status
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: The retained record states that the page for the 2014 BSH document and its 2024 update announce replacement of B12-related guidance by NICE NG239. The old document is not presented as unchanged current guidance. The full original guideline and exact diagnostic criteria were not read in this review.
Record level: Notice of a historical guideline's version and replacement status; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full official web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S09 · NICE NG239: Vitamin B12 deficiency in over 16s—diagnosis and management

Source

Material type: NICE recommendations URL linked by BSH; body text not obtained at that time
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: The identity and official link of NG239 are linked to BSH's replacement notice. Historical direct access to the recommendations' body text failed, and exact B12/MMA cutoffs or treatment instructions could not be extracted. This is not used as evidence of current access, reading of the body text or verification of the latest content.
Record level: NICE recommendations URL linked by BSH; body text not obtained at that time; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full official web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S10 · ClinicalTrials.gov NCT04024254

Source

Material type: Registry shell for the same olaparib study
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: The identifier NCT04024254 is linked to S02 Methods. Registration timing, amendments and current status were not independently certified in the historical review, and history, results and protocol contents were not obtained. The paper and registration for the same study are not counted as two independent trials.
Record level: Registry shell for the same olaparib study; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full registry web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.
Full study protocol and analysis plan Material URL unverified	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. The current record has no direct URL for the relevant full text/protocol. A bibliographic URL is not converted into a full-text download link. This does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S11 · Flamingo Pharma folic acid 5 mg tablet SmPC, text revised 20 May 2026

Source

Material type: Official labeling for a single-ingredient folic acid product
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: The indication of folate-deficient megaloblastic anemia and the adult label regimen of 5 mg/day for 4 months for a single-ingredient oral folic acid 5 mg tablet were preserved. These belong to that product's labeling, not an eligible trial regimen, Hb effect or individual instruction. The B12/undiagnosed-anemia warning, gastrointestinal/allergic, medication and pregnancy contexts, and the 2026 version were linked separately.
Record level: Official labeling for a single-ingredient folic acid product; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full official web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S12 · Swiss Federal Office of Public Health 2023 HTA: Folate Testing

Source

Material type: Official HTA of the clinical utility of folate testing
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: The 2023 Swiss HTA concerns the clinical utility of folate testing itself. Historical reading of selected narrative sections and a screenshot failure are preserved; numerical appendices/diagnostic cutoffs were not extracted. Gaps in testing evidence are not converted into ineffectiveness of replacement treatment or absence of treatment research.
Record level: Official HTA of the clinical utility of folate testing; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full official HTA report Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

S13 · Existing record 121: broad anemia, pregnancy and cardiovascular folic acid claims

Source

Material type: Pregnancy-review citation inherited from historical record 121
Materials actually read: The relevant summary and bibliographic record in the stored manuscript were checked. The linked external source material was not read in this review.
Findings recorded in the stored summary: Only the reused citation record from historical 121 in the current 3108 was read. It is a lead to the review URL and identity for PMID 23543547; pregnancy prevention and the historical combined-claim page are not counted as replications of isolated-deficiency treatment in nonpregnant people. The original 121, review and included trials were not reopened in this review.
Record level: Pregnancy-review citation inherited from historical record 121; within the retained scope of the original review dated 2026-09-15, not a reading of clinical source material in this review.
Study overlap and independent replication: Only currently retained study/material relationships were linked. The same paper, registration, historical review and official documents are not counted as independent direct trials.

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Full bibliographic/abstract web document Open material ↗	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. This is the retained entry URL for the material, not successful access, acquisition or reading in this review. It does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.
Full text of the review paper Material URL unverified	Currently unverified (no external lookup)	Access not attempted	Not read	Local summaries/historical access flags are distinguished from the fact that external material has not been read in the current review. The current record has no direct URL for the relevant full text/protocol. A bibliographic URL is not converted into a full-text download link. This does not mean that external source material was accessed, obtained or read in this review. Stored manuscripts and external source material are distinguished.

Report counts versus independent study counts

These are links among reports in the stored manuscript. FAM-GOLDING-2014 (S01): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / FAM-OLAPARIB-NCT04024254 (S02, S10): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / FAM-CLARKE-2010 (S03): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / FAM-SHEEHY-1961 (S04): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / OFFICIAL-ODS-FOLATE (S05): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / FAM-OBEID-2017 (S06): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / FAM-NOZARI-2019 (S07): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / OFFICIAL-BSH-STATUS (S08): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / OFFICIAL-NICE-NG239 (S09): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / OFFICIAL-FOLIC-ACID-LABEL (S11): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / OFFICIAL-SWISS-FOLATE-HTA (S12): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. / FAM-LASSI-PREGNANCY-REVIEW (S13): The current evidence study_id was linked to bibliographic relationships, shared registrations and historical reused citations. No inferences were made about an absent collection or the number of direct studies. Human data exist, but directly eligible Hb results remain unverified within the retained review. This does not mean a worldwide absence of research or an effect of 0. Family labels are not summed as independent trial counts or participant counts.

Review criteria

Version NGM-v3108-ISOLATED-FOLATE-ANEMIA-HB-1.1 · Criteria record date 2026-10-05. These are Chamgap's own application conditions, informed by the referenced methods. They do not constitute official assessment-tool certification or a new efficacy score.

N01 · Which population with deficiency, oral folic acid comparison and Hb outcome does this table address?

Required materials and conditions: The current original claim and specifications for laboratory confirmation, B12 exclusion, ingredient, route, background care and control, Hb and time point
Conditions for verification: Fix the question as a between-group Hb comparison at a predefined time in isolated folate-deficiency anemia, with oral folic acid as the sole addition versus no added folic acid under the same background care.
Requirement and applicability: Required
Application exceptions: Verifying the identity of the question does not verify the existence of an eligible comparison or the magnitude of the treatment effect.
Why this condition is needed: Required to distinguish the historical combined claims about anemia, pregnancy and cardiovascular outcomes from the current single Hb question.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed

N02 · How were isolated folate deficiency and megaloblastic anemia confirmed, and how was B12 deficiency excluded?

Required materials and conditions: The original diagnostic framework, serum/RBC folate, Hb/MCV, marrow, B12 and functional markers, and exclusion criteria
Conditions for verification: Cross-check confirmation of diagnosis and exclusion of mixed deficiency in the selected population against the actual locations of the test records.
Requirement and applicability: Required
Application exceptions: Unverified test details do not establish that no diagnosis was made. Inaccessible NICE cutoffs are not inserted as new criteria.
Why this condition is needed: Required to avoid defining a confirmed isolated-deficiency population solely from low folate or an anemia heading.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application

N03 · Were groups with other etiologies, including pregnancy, mixed deficiencies, drugs, alcohol and malabsorption, distinguished?

Required materials and conditions: Information on diagnosis by etiology, coexisting deficiencies, pregnancy/lactation, age, liver and kidney status, drugs and malabsorption
Conditions for verification: Specify the differences between the question about isolated deficiency in nonpregnant adults and the actual populations in related material.
Requirement and applicability: Required
Application exceptions: Recovery in groups with other etiologies is preserved, and the reasons for exclusion are not used to claim no effect in those groups.
Why this condition is needed: Required to avoid combining material with different etiologies and treatment conditions solely because it shares the name anemia.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed

N04 · Were folic acid and the actual dosage form, manufacturer and product in an eligible comparison verified?

Required materials and conditions: Original records of chemical form, salt, sole active ingredient, dosage form, manufacturer, brand, batch and purity
Conditions for verification: Separate the folic acid specified in the question from the extent to which the product in an actual comparison has been verified.
Requirement and applicability: Required
Application exceptions: The identity of the official 5 mg tablet belongs to that product's labeling; it is not assumed to be the same product used in an eligible trial.
Why this condition is needed: Required to avoid treating folinic acid, 5-MTHF and combination products as the same intervention.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed

N05 · Were the dose, dosing frequency, treatment duration and exposure of an eligible oral regimen verified?

Required materials and conditions: Original data on route, daily dose, dosing frequency, total exposure, treatment duration and concurrent supplementation for each eligible group
Conditions for verification: Link only exposure from the actual comparison, and attribute labeled doses and doses used in groups with other etiologies separately.
Requirement and applicability: Required
Application exceptions: The route in the question is oral, but the actual dose and duration of an eligible regimen remain unverified. No individual dose is specified.
Why this condition is needed: Required to avoid turning other routes, product labeling or doses from related trials into the regimen for the main question.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed

N06 · Were background treatment apart from folic acid and a control without added folic acid actually compared?

Required materials and conditions: Original records of background treatment, concurrent supplementation, diet, transfusion, rescue treatment and the control without added folic acid for each group
Conditions for verification: Link the contrast for added folic acid under the same background care to the actual differences in background care.
Requirement and applicability: Required
Application exceptions: Shared treatment is not itself a reason for exclusion. Withholding treatment is not assumed to be acceptable, and ethically appropriate comparisons are distinguished.
Why this condition is needed: Required to avoid attributing before-and-after recovery or asymmetric treatment changes to a between-group effect of folic acid alone.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M08 §8.1–8.2.3; internal application; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application

N07 · Is the primary outcome the between-group change in Hb, distinguished from MCV, reticulocytes, folate and other measures?

Required materials and conditions: Hb definition, change/final values, units, direction of comparison, predefined follow-up time and a list of other endpoints
Conditions for verification: Distinguish the between-group difference in change in blood Hb from an adjusted difference in final values, and keep g/dL, g/L and time points separate.
Requirement and applicability: Required
Application exceptions: Trials of survival or transfusion events are not unconditionally required for a question about Hb itself. Such extensions require separate evidence.
Why this condition is needed: Required to avoid substituting other biochemical recovery for Hb comparison values.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim

N08 · Can the fixed Hb follow-up time in an eligible comparison be distinguished from treatment and observation durations?

Required materials and conditions: Original registration/protocol records of the primary Hb time point, measurement schedule, treatment, discontinuation and follow-up duration
Conditions for verification: Distinguish the predefined follow-up time of an eligible comparison from time coordinates in related material.
Requirement and applicability: Required
Application exceptions: Golding's days 586, 588 and 772 are study-day coordinates, not a prescribed general recovery timetable.
Why this condition is needed: Required to avoid turning coordinates measured from the start of a study or a product's treatment duration into the fixed time point of a between-group comparison.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed

N09 · Were Hb measurement and differences in transfusion, bleeding and testing that affect anemia verified?

Required materials and conditions: Records of the Hb assay, units, specimen/collection schedule, assessor blinding, transfusion, bleeding and changes by group in an eligible comparison
Conditions for verification: Link Hb measurement conditions and the effects of other treatment or physiological changes to the actual comparison.
Requirement and applicability: Required
Application exceptions: Failure to verify a measurement method in the current material is not expanded into a claim that it was unreported throughout the original paper.
Why this condition is needed: Required to distinguish measurement and clinical conditions contributing to Hb change from the contribution of folic acid.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application

N10 · Were the actual comparative design, allocation and baseline balance in the isolated-deficiency population verified?

Required materials and conditions: Original records of selection, design, allocation/concealment, baseline status, background care and control, and denominators in an eligible comparison
Conditions for verification: Separate the currently known designs from the unverified status of a direct comparison in the isolated-deficiency population.
Requirement and applicability: Required
Application exceptions: Prospective observations are also preserved. Randomized placebo comparisons are not newly designated as the sole permissible evidence for replacement treatment.
Why this condition is needed: Required to distinguish the existence of human research from a direct comparative design for the selected question.
Referenced methods: M08 §8.1–8.2.3; internal application; M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed

N11 · Were the participant count and the number of analytical replicates in Golding's self-experiment distinguished?

Required materials and conditions: Original records of the self-experiment's design, participant/randomized/control counts and repeated tests
Conditions for verification: Link the depletion-and-recovery trajectory of one person to the implications of having no concurrent control.
Requirement and applicability: Required
Application exceptions: Recovery in 1 person is retained as information but is not converted into a between-group effect or population incidence.
Why this condition is needed: Required to avoid counting analytical replicates or specimens as new participants or independent comparisons.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.1–8.2.3; internal application; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application

N12 · To what extent were Golding's Hb recovery timing and graph values read?

Required materials and conditions: The depletion-and-repletion timeline, reported Hb trajectory and extent of reading of the original graph
Conditions for verification: Retain the study-day coordinates and recovery narrative without turning them into a quantitative between-group comparison.
Requirement and applicability: Required
Application exceptions: The graphs are not digitized, and the Hb value at the nadir is not reconstructed.
Why this condition is needed: Required to preserve favorable recovery without converting an uncontrolled trajectory into an effect estimate.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application

N13 · Were Golding's resumption of normal diet and concurrent B12 use distinguished from the contribution of folic acid?

Required materials and conditions: Original records of diet, folate, methylcobalamin, B12 tests and times of changes
Conditions for verification: Link concurrent B12 at 1000 µg/day and resumption of diet to the context of the self-experiment.
Requirement and applicability: Required
Application exceptions: B12 monitoring and methylcobalamin administration are not treated as equivalent to diagnostic exclusion.
Why this condition is needed: Required to avoid attributing simultaneous dietary changes and cointerventions to the effect of folic acid alone.
Referenced methods: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed

N14 · Is Shammo's cancer/olaparib population the same as a population with confirmed isolated folate-deficiency anemia?

Required materials and conditions: Original data on cancer/drugs, anemia/folate diagnosis, and the stratum with megaloblastic anemia and B12 deficiency excluded
Conditions for verification: Explain the differences between the olaparib-related population and the confirmed isolated-deficiency population, and the unverified status of the separately defined stratum.
Requirement and applicability: Required
Application exceptions: The randomized component in the related material is not disregarded; the population mismatch and the unverified effect are retained separately.
Why this condition is needed: Required to avoid transferring a comparison in cancer- or drug-induced anemia to isolated nutritional deficiency.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application

N15 · Were the 9 enrolled participants, the 2+2 allocated participants and the 12-month completion denominator distinguished?

Required materials and conditions: Original flow records for consent, enrollment, randomization, nonrandomization, completion and Hb analysis by group
Conditions for verification: Attribute each count to its own stage: 10 consented, 9 enrolled, 4 allocated as 2+2, 5 nonrandomized, and 5 completing 12 months in the entire cohort.
Requirement and applicability: Required
Application exceptions: The total of 9 participants and the 5 completers are not the Hb analysis counts for each group. Analysis denominators absent from the original text are not filled in by arithmetic.
Why this condition is needed: Required to avoid using the entire cohort as the denominator for randomized Hb analyses.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application

N16 · To which trial do Shammo's 1 mg/day dose and folate/Hb allocation and rescue criteria belong?

Required materials and conditions: The original trial dose, folate/Hb allocation criteria, rescue policy and actual use by group
Conditions for verification: Attribute oral 1 mg/day, folate <7 ng/mL and Hb <12 g/dL, and rescue at Hb <10 g/dL to the oncology trial.
Requirement and applicability: Required
Application exceptions: Rescue at Hb <10 g/dL is this trial's original protocol, not a threshold for withholding treatment from patients generally.
Why this condition is needed: Required to avoid extending an oncology trial's protocol into general diagnostic confirmation criteria or a treatment regimen.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed

N17 · Were Shammo's change from the placebo plan and the actual control without supplementation distinguished?

Required materials and conditions: The original plan, reasons for changes, open-label/blinding status, actual control without supplementation and analysis documents
Conditions for verification: Link the abandonment of placebo and the comparison without supplementation to the actual design, and distinguish the amendment history.
Requirement and applicability: Required
Application exceptions: The cost-related change is recorded, but the lack of an obtained protocol is not converted into a confirmed finding of selective reporting.
Why this condition is needed: Required to avoid presenting the initially planned placebo as an actual blinded trial.
Referenced methods: M08 §8.1–8.2.3; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed

N18 · Were the phase IV and phase II/single-arm labels recorded in Shammo's original text preserved without arbitrarily harmonizing them?

Required materials and conditions: The relevant original pages, design wording, corrections or author explanations
Conditions for verification: Preserve the discrepancy between p.1/3 phase IV and the p.2 phase II/single-arm template, together with their locations.
Requirement and applicability: Required
Application exceptions: The wording conflict is reported in the currently retained citation; the original full text was not independently rechecked in this review.
Why this condition is needed: Required to avoid inferring one actual phase from inconsistent design labels within the same report.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.1–8.2.3; internal application

N19 · Were Shammo's interpretation of secondary Hb results and olaparib dose reduction kept from being converted into a between-group effect?

Required materials and conditions: Secondary Hb results, medication changes by group, formal Hb estimates/variance/time points and the original protocol
Conditions for verification: Attribute the primary frequency/timing of folate deficiency, secondary Hb and olaparib dose reduction in controls to their respective roles.
Requirement and applicability: Required
Application exceptions: The authors' interpretation of Hb is preserved, but nonsignificance or unverified quantitative information is not used as equivalence or an effect of 0.
Why this condition is needed: Required to avoid turning folate recovery, author narratives and asymmetric medication changes into a formal Hb effect.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application

N20 · How were Clarke's case and Sheehy's tropical-sprue material preserved?

Required materials and conditions: Case etiology, cointerventions/transfusion, administration/control, B12 exclusion, Hb values and the actual extent of access
Conditions for verification: Specify the differences between Clarke's 1-person case with mixed etiologies and Sheehy's malabsorption/dose-titration setting.
Requirement and applicability: Required
Application exceptions: Limited full-text access is not expanded into a claim of nonreporting in the original text or absence of research in this review.
Why this condition is needed: Required to preserve related hematologic recovery without counting it as replication in isolated deficiency.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed

N21 · Does Obeid's folate-marker study in nonpregnant women provide an Hb treatment result in confirmed anemia?

Required materials and conditions: Actual anemia diagnosis, baseline status, Hb outcomes, folate markers and the location of the selection information
Conditions for verification: Record the difference between biomarker supplementation material in people without anemia and the treatment question in confirmed megaloblastic anemia.
Requirement and applicability: Required
Application exceptions: An exclusion recorded at index level is not converted into a quality review of the entire original full text or a finding of no effect.
Why this condition is needed: Required to avoid inferring a treatment effect solely from the shared characteristic of being nonpregnant or from folate recovery.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim

N22 · Can Nozari's combined B12+folic acid intervention in MS be separated into an effect of folic acid alone?

Required materials and conditions: The MS population, B12/folic acid interventions by group, Hb/anemia/quality-of-life outcomes and a contrast with a sole added ingredient
Conditions for verification: Link MS and the addition of two active ingredients to their differences from the main population/intervention.
Requirement and applicability: Required
Application exceptions: The favorable context of the combination data is preserved, and effects of individual ingredients are not arbitrarily disentangled.
Why this condition is needed: Required to avoid attributing combination results to folic acid alone when both the population and the added active ingredients differ.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application

N23 · Were the pregnancy review and trials from historical record 121 kept from being counted as independent replications of replacement treatment in adults?

Required materials and conditions: The actual populations and prevention/treatment questions of the review/included trials, and links to original data
Conditions for verification: Distinguish a pregnancy-prevention review from Hb treatment in nonpregnant people with isolated deficiency, and do not infer the number of direct replications.
Requirement and applicability: Required
Application exceptions: The original file for historical record 121 was not read in this review; only the reused citation record in the current 3108 was read.
Why this condition is needed: Required to avoid double-counting a historical combined-claim page and trials included in a review as replications of the new isolated-deficiency treatment question.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application

N24 · Were the direct Hb difference in change, adjusted difference in final values, and SD/SE, CI and P verified?

Required materials and conditions: Original tables of Hb values/changes, units, n and SD/SE for each eligible group, the estimation model, CI and P
Conditions for verification: Separate between-group change from the adjusted difference in final values, and specify that variance, intervals and tests remain unverified.
Requirement and applicability: Required
Application exceptions: Keep the variance type and CI unverified when they are unverified, and do not determine precision from sample size alone.
Why this condition is needed: Required to avoid filling absent direct values with 0 or reconstructing them from graphs or other markers.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application

N25 · Were ITT/PP, completion/analysis denominators, missing data and Hb analysis in the main comparison verified?

Required materials and conditions: Flow, Hb measurement/analysis n, ITT/PP, reasons for and handling of missing data, and sensitivity analyses for each eligible group
Conditions for verification: Separate allocation, completion and analysis, and link the selected effect of interest to the unverified status of the actual analysis.
Requirement and applicability: Required
Application exceptions: Unverified analysis details are not converted into randomization failure, confirmed selective reporting or 0 missing observations.
Why this condition is needed: Required to avoid turning enrollment, allocation or before-and-after measurement counts into actual Hb analysis denominators.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application

N26 · Were the clinical importance of Hb and questions about symptoms, transfusion and survival distinguished?

Required materials and conditions: A justified criterion for an important Hb difference in the relevant population, and direct outcomes for symptoms, transfusion and quality of life/survival
Conditions for verification: Distinguish the degree to which an Hb importance criterion is verified from the degree to which separate event evidence is verified.
Requirement and applicability: Supplementary; required for claims about importance or extension to event outcomes
Application exceptions: When the original question concerns Hb values, survival trials are not imposed as mandatory. No universal MCID, minimum participant count or duration is newly invented.
Why this condition is needed: Required to avoid extending the clinical scope of treatment benefit solely from a laboratory change.
Referenced methods: M15 §15.3.1–15.3.3; internal application; M03 §3.2.4; internally defined boundaries for extending the claim; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed

N27 · To what extent were each report's family and funding/product/conflict-of-interest information verified?

Required materials and conditions: Unique-study/reused-citation relationships and original wording on research funding, product provision and author disclosures
Conditions for verification: Link evidence study_id, shared registration and material roles, and leave funding unverified where the original text is unavailable.
Requirement and applicability: Supplementary; required for a claim of independence
Application exceptions: Unverified conflicts of interest are not treated as independent support, and product documents are identified as manufacturer material.
Why this condition is needed: Required to avoid inferring independent replication or verified funding solely from 13 reports and location references.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items

N28 · Were the registry shell and the original protocol/SAP, amendment history and current status distinguished?

Required materials and conditions: The original NCT04024254 registration/history, protocol, SAP, Hb hierarchy/time points and reasons for amendments
Conditions for verification: Separate the retained identifier linkage from unverified registration timing, history and current status.
Requirement and applicability: Required
Application exceptions: Limited access to the original protocol does not establish nonregistration or selective reporting. It is also not a failed access attempt in this review.
Why this condition is needed: Required to avoid turning the existence of a registration number into proof of preregistration, endpoint agreement or current completion.
Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application

N29 · Were BSH's replacement notice and the unverified NICE details distinguished?

Required materials and conditions: BSH version/update notices, the identity of NICE NG239 and the actual original diagnostic/treatment recommendations
Conditions for verification: Separate the 2024 replacement notice for the 2014 document from the unverified scope of the original recommendations.
Requirement and applicability: Supplementary; required for diagnostic and safety applications
Application exceptions: The original NICE recommendations were not read in this review, and the earlier failure to access the body text is retained as a historical record.
Why this condition is needed: Required to avoid presenting an old guideline as unchanged current guidance or filling in diagnostic criteria that have not been read.
Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied

N30 · Was the Swiss HTA's evidence on testing utility kept from being transferred into a claim of no effect of folic acid treatment?

Required materials and conditions: The HTA's question about the clinical utility of testing, original sections/pages and distinction from the treatment context
Conditions for verification: Separate the question of folate testing from the question of Hb treatment in isolated deficiency.
Requirement and applicability: Required
Application exceptions: Historical reading of some HTA narrative does not verify values in the original appendices or diagnostic cutoffs.
Why this condition is needed: Required to avoid using a lack of evidence for the testing question to claim that replacement-treatment research or all human research is absent.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed

N31 · Were recognized replacement treatment and the dose on the S11 label distinguished from a direct comparative effect?

Required materials and conditions: S11 product identity, indication, labeled dose/duration and version, and the identity of an eligible trial
Conditions for verification: Retain recognized replacement treatment and product labeling, while separating them from verified between-group results and regimens.
Requirement and applicability: Required
Application exceptions: An unverified direct effect is not interpreted as recognized treatment being unnecessary or as advice to delay treatment.
Why this condition is needed: Required to avoid turning an authorized indication or 5 mg/4 months into a trial effect estimate or individual dosing instructions.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

N32 · Were the original nonapplication of RE, allowance for prospective observation and prohibition on withholding treatment retained unchanged?

Required materials and conditions: The original reasons for the RE decision, objective diagnosis/replacement mechanism, prospective observation and the extent of verification of the five gates at that time
Conditions for verification: Preserve the allowance for prospective observation and the gates that were not established, and record the original RE_eligible=false unchanged.
Requirement and applicability: Required
Application exceptions: No new determination is made about whether RE is met or whether no treatment is ethically permissible. There is no assumption that withholding treatment is acceptable.
Why this condition is needed: Required to avoid turning the exception logic of the current original verdict into a new score, a mandatory placebo requirement or treatment delay.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M08 §8.1–8.2.3; internal application; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

N33 · Was improvement in Hb distinguished from resolution of neurological problems due to B12 deficiency?

Required materials and conditions: S11 contraindications and precautions for B12 deficiency/undiagnosed anemia, and actual neurological-harm definitions and exposure/denominator data
Conditions for verification: Record warnings about masking B12 findings and delayed recognition separately from Hb recovery and unverified frequency.
Requirement and applicability: Supplementary; required for safety boundaries
Application exceptions: The official warning is product context and does not determine incidence or individual risk in the isolated-deficiency population.
Why this condition is needed: Required to avoid implying that hematologic improvement means resolution of B12 deficiency or neurological safety.
Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied

N34 · Were gastrointestinal and allergic reactions and interactions distinguished from actual event denominators in the eligible population?

Required materials and conditions: Original data on AE/SAE, discontinuation, exposure/duration, collection methods, people with events/event counts and concomitant drugs for each eligible group
Conditions for verification: Distinguish S11's gastrointestinal/allergic and antiepileptic/methotrexate context from the gap in direct event rates.
Requirement and applicability: Supplementary; required for frequency/safety claims
Application exceptions: The statuses Not read and Unverified are not converted into 0 people with adverse reactions/SAE/discontinuation.
Why this condition is needed: Required to avoid turning a product's reaction list into comparative event rates or absence of risk in the main population.
Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application

N35 · Can safety/efficacy be extended to high doses, long-term use, liver or kidney disease, cancer, malabsorption, pregnancy/lactation and children?

Required materials and conditions: Actual exposure/effect by population, dose and duration, rare/long-term harms, and drug/underlying-disease data
Conditions for verification: Record the question about nonpregnant adults with isolated deficiency separately from the unverified scope for each special population.
Requirement and applicability: Supplementary; required for extension claims
Application exceptions: Studies in every special population are not imposed as mandatory for the original Hb question, and individual dosing instructions are not provided.
Why this condition is needed: Required to avoid extending related product context or brief recovery to safety/efficacy in all populations.
Referenced methods: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied; M03 §3.2.1; detailed population criteria are internally designed

N36 · Was historical access for the 13 bibliographic records distinguished from reading local summaries in this review?

Required materials and conditions: Material type, URL, historical access_level/flag, dates and original locations for each report, and exact current stored-summary anchors
Conditions for verification: Separate actual reading, acquisition and access status by material type into current and historical records, and leave records without access dates empty.
Requirement and applicability: Required
Application exceptions: Access to all external material is currently unattempted, and none of it has been read in this review; historical failures are not presented as failures in this review.
Why this condition is needed: Required to avoid upgrading original full-text access flags and links into full-text reading in this review.
Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

N37 · Were the original ?/empty values, axes, safety and publication records distinguished from the new criteria statuses?

Required materials and conditions: Original grade/score/axes, calculation, evidence_status, publication/server metadata and the scope of the new table
Conditions for verification: Preserve the original verdict values byte for byte, and separate them from criteria statuses and the fact that this public version has not been deployed.
Requirement and applicability: Required
Application exceptions: The original first_published_at is the content baseline date; server_deployed and server_write=false are retained records.
Why this condition is needed: Required to avoid carrying over the original score or internal deployment metadata as new efficacy, safety or completed public website publication.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

N38 · What would actually update the gaps within the retained search scope of 2026-09-15?

Required materials and conditions: New direct Hb results, actual original texts/protocols, corrections/retractions, and evidence of numerical, classification, diagnostic and safety changes
Conditions for verification: Record the original cutoff date, incompleteness, unchanged ID/URL, reasons for changes and re-review of linked rows.
Requirement and applicability: Required
Application exceptions: This is not a new search, correction/retraction lookup, calculation or reassessment. Revision of criteria and addition of evidence are separate events.
Why this condition is needed: Required to avoid turning a limited current value into an up-to-date exhaustive search or a claim of permanent absence.
Referenced methods: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application

Referenced methods and the sections actually reviewed

M03 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13

Referenced principle: Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.
Extent of review: The copies, SHA values and methodological principles retained from 1585 were reused as historical material. This is not new reading of full methodological texts, application of an official tool or clinical certification in this review.

M04 · Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03

Official methodology · §4.5, §4.6.1–4.6.3, MECIR C42

Referenced principle: Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.
Extent of review: The copies, SHA values and methodological principles retained from 1585 were reused as historical material. This is not new reading of full methodological texts, application of an official tool or clinical certification in this review.

M08 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §8.1–8.2.3, Table 8.2.a

Referenced principle: Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.
Extent of review: The copies, SHA values and methodological principles retained from 1585 were reused as historical material. This is not new reading of full methodological texts, application of an official tool or clinical certification in this review.

M15 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §15.2.4, §15.3.1–15.3.3

Referenced principle: Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.
Extent of review: The copies, SHA values and methodological principles retained from 1585 were reused as historical material. This is not new reading of full methodological texts, application of an official tool or clinical certification in this review.

M19 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §19.1.2, §19.2.1–19.2.4

Referenced principle: Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.
Extent of review: The copies, SHA values and methodological principles retained from 1585 were reused as historical material. This is not new reading of full methodological texts, application of an official tool or clinical certification in this review.

What the statuses mean

Met: The relevant criterion was verified within this question and the retained scope. This does not establish efficacy.
Partly verified: Some records are verified, while gaps in direct criteria/data remain.
Unverified: The required direct values/criteria have not been verified within the current scope.
Not met: The population/ingredient/endpoint in the currently verified material does not match the selected direct criteria.
Conflicting information: This is a wording discrepancy within the same report, explicitly recorded in the original retained record. It is not independent verification of the original full text in this review.
Not read: The relevant external material was not actually read in this review.

Change history

2026-11-05 · Public page/material version 1.0

The public-facing display and data were prepared from the existing 38 items. No new clinical search, change in verification status or scoring was performed.

The stored-material review date (2026-10-05) and original evidence cut-off (2026-09-15) were retained unchanged.

Researcher downloads

These materials provide the same evidence, scope and verification status as this page.

View all item details

N01 · Which population with deficiency, oral folic acid comparison and Hb outcome does this table address?

Current findings: The original claim is an increase in Hb in confirmed folate-deficient megaloblastic anemia. It was fixed as one comparison with oral folic acid as the sole addition under the same background care, and subclaims is an empty list.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The original claim was linked to the inclusion and exclusion boundaries. This does not establish efficacy or constitute a new verdict.
Reason for missing information: The actual formulation, dose, duration and between-group results of an eligible comparison remain separately unverified.
Required materials and conditions: The current original claim and specifications for laboratory confirmation, B12 exclusion, ingredient, route, background care and control, Hb and time point
Materials to obtain first: The current original claim and specifications for laboratory confirmation, B12 exclusion, ingredient, route, background care and control, Hb and time point
Further research: Future comparisons should first specify this population and the Hb effect of interest, and report other etiologies and endpoints as separate questions.
Remaining uncertainty: The actual formulation, dose, duration and between-group results of an eligible comparison remain separately unverified.
Conditions for verification: Fix the question as a between-group Hb comparison at a predefined time in isolated folate-deficiency anemia, with oral folic acid as the sole addition versus no added folic acid under the same background care.
Why this condition is needed: Required to distinguish the historical combined claims about anemia, pregnancy and cardiovascular outcomes from the current single Hb question.
Application exceptions: Verifying the identity of the question does not verify the existence of an eligible comparison or the magnitude of the treatment effect.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed

Related sources

N02 · How were isolated folate deficiency and megaloblastic anemia confirmed, and how was B12 deficiency excluded?

Current findings: The question requires laboratory-confirmed isolated deficiency and exclusion of B12 deficiency, but the diagnostic cutoffs in an eligible comparison remain unverified. Golding's tests, marrow findings and B12 monitoring provide context; they are not themselves between-group results for this population.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The population specified by the question and some human test records are verified, but the confirmation criteria and separately identified population in an eligible comparison have not been verified.
Reason for missing information: Test values, thresholds and the population stratum with B12 deficiency excluded cannot be linked to a direct Hb comparison.
Required materials and conditions: The original diagnostic framework, serum/RBC folate, Hb/MCV, marrow, B12 and functional markers, and exclusion criteria
Materials to obtain first: The original diagnostic framework, serum/RBC folate, Hb/MCV, marrow, B12 and functional markers, and exclusion criteria
Further research: Record the diagnostic and B12-exclusion procedures, and separate results for the confirmed isolated-deficiency population from those for other deficiency strata.
Remaining uncertainty: Test values, thresholds and the population stratum with B12 deficiency excluded cannot be linked to a direct Hb comparison.
Conditions for verification: Cross-check confirmation of diagnosis and exclusion of mixed deficiency in the selected population against the actual locations of the test records.
Why this condition is needed: Required to avoid defining a confirmed isolated-deficiency population solely from low folate or an anemia heading.
Application exceptions: Unverified test details do not establish that no diagnosis was made. Inaccessible NICE cutoffs are not inserted as new criteria.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application

Related sources S01 S08 S09

N03 · Were groups with other etiologies, including pregnancy, mixed deficiencies, drugs, alcohol and malabsorption, distinguished?

Current findings: Material on cancer/olaparib, alcohol/liver disease/bleeding, tropical sprue, pregnancy and combinations with B12 was not pooled with direct comparisons in adults with isolated deficiency. Pediatric cases and mixed B12/iron deficiency, renal disease, hemolysis, aplasia and inflammatory causes also remain outside that boundary.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The population differences and reasons for exclusion stated in the original text were preserved. Extension to other populations has not been verified.
Reason for missing information: The direct Hb effect in this population stratum and effects in groups with other etiologies are not interchangeable.
Required materials and conditions: Information on diagnosis by etiology, coexisting deficiencies, pregnancy/lactation, age, liver and kidney status, drugs and malabsorption
Materials to obtain first: Information on diagnosis by etiology, coexisting deficiencies, pregnancy/lactation, age, liver and kidney status, drugs and malabsorption
Further research: Future studies should distinguish mixed deficiencies and special etiologies in advance and present direct comparisons separately for each population stratum.
Remaining uncertainty: The direct Hb effect in this population stratum and effects in groups with other etiologies are not interchangeable.
Conditions for verification: Specify the differences between the question about isolated deficiency in nonpregnant adults and the actual populations in related material.
Why this condition is needed: Required to avoid combining material with different etiologies and treatment conditions solely because it shares the name anemia.
Application exceptions: Recovery in groups with other etiologies is preserved, and the reasons for exclusion are not used to claim no effect in those groups.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed

Related sources S02 S03 S04 S07 S13

N04 · Were folic acid and the actual dosage form, manufacturer and product in an eligible comparison verified?

Current findings: The chemical form in the question is folic acid, distinguished from folinic acid and 5-MTHF. The salt, dosage form, brand, manufacturer, batch and purity in an eligible comparison remain unverified. The 5 mg oral tablet in S11 was retained only as product context.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The chemical form specified by the question and information about an official product are available, but the product in an eligible comparison has not been verified.
Reason for missing information: Official product labeling cannot be carried over as proof of identity with the actual trial product.
Required materials and conditions: Original records of chemical form, salt, sole active ingredient, dosage form, manufacturer, brand, batch and purity
Materials to obtain first: Original records of chemical form, salt, sole active ingredient, dosage form, manufacturer, brand, batch and purity
Further research: Record the identifiable single-ingredient folic acid product and each group's product, batch, purity and other active ingredients.
Remaining uncertainty: Official product labeling cannot be carried over as proof of identity with the actual trial product.
Conditions for verification: Separate the folic acid specified in the question from the extent to which the product in an actual comparison has been verified.
Why this condition is needed: Required to avoid treating folinic acid, 5-MTHF and combination products as the same intervention.
Application exceptions: The identity of the official 5 mg tablet belongs to that product's labeling; it is not assumed to be the same product used in an eligible trial.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed

Related sources S11

N05 · Were the dose, dosing frequency, treatment duration and exposure of an eligible oral regimen verified?

Current findings: The dose, dosing frequency and treatment duration in an eligible comparison remain unverified. The 1 mg/day used in the olaparib population and the 5 mg/day for 4 months in the S11 label are not used as verified regimens for this question.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The oral route is specified in the question, but the actual dose and duration in an eligible comparison could not be verified.
Reason for missing information: The optimal dose, duration, dosing schedule or equivalence of other routes cannot be determined.
Required materials and conditions: Original data on route, daily dose, dosing frequency, total exposure, treatment duration and concurrent supplementation for each eligible group
Materials to obtain first: Original data on route, daily dose, dosing frequency, total exposure, treatment duration and concurrent supplementation for each eligible group
Further research: Record actual use, adherence and concurrent supplementation for the sole oral addition, and directly compare justified dose/duration questions.
Remaining uncertainty: The optimal dose, duration, dosing schedule or equivalence of other routes cannot be determined.
Conditions for verification: Link only exposure from the actual comparison, and attribute labeled doses and doses used in groups with other etiologies separately.
Why this condition is needed: Required to avoid turning other routes, product labeling or doses from related trials into the regimen for the main question.
Application exceptions: The route in the question is oral, but the actual dose and duration of an eligible regimen remain unverified. No individual dose is specified.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed

Related sources S02 S11

N06 · Were background treatment apart from folic acid and a control without added folic acid actually compared?

Current findings: The question specifies a control without added folic acid under the same background treatment, but an actual eligible comparison remains unverified. Golding had no concurrent control, and Shammo's controls also underwent olaparib dose reduction.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The current related material alone cannot verify a between-group contrast under the same background care in the isolated-deficiency population.
Reason for missing information: The extent to which concurrent diet, drugs, transfusion and rescue treatment contributed to the outcome remains unverified.
Required materials and conditions: Original records of background treatment, concurrent supplementation, diet, transfusion, rescue treatment and the control without added folic acid for each group
Materials to obtain first: Original records of background treatment, concurrent supplementation, diet, transfusion, rescue treatment and the control without added folic acid for each group
Further research: Define the ethically permissible comparison and effect of interest, and report background treatment, rescue treatment and changes by group.
Remaining uncertainty: The extent to which concurrent diet, drugs, transfusion and rescue treatment contributed to the outcome remains unverified.
Conditions for verification: Link the contrast for added folic acid under the same background care to the actual differences in background care.
Why this condition is needed: Required to avoid attributing before-and-after recovery or asymmetric treatment changes to a between-group effect of folic acid alone.
Application exceptions: Shared treatment is not itself a reason for exclusion. Withholding treatment is not assumed to be acceptable, and ethically appropriate comparisons are distinguished.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M08 §8.1–8.2.3; internal application; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application

Related sources S01 S02

N07 · Is the primary outcome the between-group change in Hb, distinguished from MCV, reticulocytes, folate and other measures?

Current findings: The primary outcome is the between-group difference in change in blood Hb at a predefined time; an appropriately adjusted difference in final values is separate. MCV, reticulocytes, folate concentrations, fatigue, transfusion and correction rates do not substitute for the primary outcome.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The boundary between the selected endpoint and other endpoints was linked to the original text. An actual Hb effect estimate has not been verified.
Reason for missing information: The original Hb values, changes, adjustment status and units in a direct comparison remain unverified.
Required materials and conditions: Hb definition, change/final values, units, direction of comparison, predefined follow-up time and a list of other endpoints
Materials to obtain first: Hb definition, change/final values, units, direction of comparison, predefined follow-up time and a list of other endpoints
Further research: Define Hb measurement and analysis in advance, and report other markers, symptoms, transfusion and correction rates as separate outcomes.
Remaining uncertainty: The original Hb values, changes, adjustment status and units in a direct comparison remain unverified.
Conditions for verification: Distinguish the between-group difference in change in blood Hb from an adjusted difference in final values, and keep g/dL, g/L and time points separate.
Why this condition is needed: Required to avoid substituting other biochemical recovery for Hb comparison values.
Application exceptions: Trials of survival or transfusion events are not unconditionally required for a question about Hb itself. Such extensions require separate evidence.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim

Related sources

N08 · Can the fixed Hb follow-up time in an eligible comparison be distinguished from treatment and observation durations?

Current findings: The fixed Hb follow-up time and the treatment and follow-up durations in an eligible comparison remain unverified. The self-experiment's coordinates—diet resumed on day 586, a nadir near day 588 and return by day 772—are not repurposed as a treatment effect at a fixed time point.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The time point in the main question was defined, but the predefined time point in an actual eligible comparison could not be verified.
Reason for missing information: No new treatment duration or mean recovery time is calculated from the observational coordinates.
Required materials and conditions: Original registration/protocol records of the primary Hb time point, measurement schedule, treatment, discontinuation and follow-up duration
Materials to obtain first: Original registration/protocol records of the primary Hb time point, measurement schedule, treatment, discontinuation and follow-up duration
Further research: Specify treatment exposure and the Hb follow-up schedule, and measure the effects of continuation and discontinuation as separate questions defined in advance.
Remaining uncertainty: No new treatment duration or mean recovery time is calculated from the observational coordinates.
Conditions for verification: Distinguish the predefined follow-up time of an eligible comparison from time coordinates in related material.
Why this condition is needed: Required to avoid turning coordinates measured from the start of a study or a product's treatment duration into the fixed time point of a between-group comparison.
Application exceptions: Golding's days 586, 588 and 772 are study-day coordinates, not a prescribed general recovery timetable.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed

Related sources S01

N09 · Were Hb measurement and differences in transfusion, bleeding and testing that affect anemia verified?

Current findings: The Hb assay, measurement schedule, transfusion/bleeding by group and assessment procedures in the fixed comparison have not been verified. Recovery in a case involving alcohol, liver disease and bleeding is not used as a comparison with matched measurement conditions.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: No eligible material is available to link direct Hb values to measurement conditions.
Reason for missing information: Measurement limitations and other factors affecting Hb change in each group of the main comparison cannot be assessed quantitatively.
Required materials and conditions: Records of the Hb assay, units, specimen/collection schedule, assessor blinding, transfusion, bleeding and changes by group in an eligible comparison
Materials to obtain first: Records of the Hb assay, units, specimen/collection schedule, assessor blinding, transfusion, bleeding and changes by group in an eligible comparison
Further research: Standardize testing and specimen schedules, transfusion/bleeding and concurrent treatment, or report the actual differences and how they were handled analytically.
Remaining uncertainty: Measurement limitations and other factors affecting Hb change in each group of the main comparison cannot be assessed quantitatively.
Conditions for verification: Link Hb measurement conditions and the effects of other treatment or physiological changes to the actual comparison.
Why this condition is needed: Required to distinguish measurement and clinical conditions contributing to Hb change from the contribution of folic acid.
Application exceptions: Failure to verify a measurement method in the current material is not expanded into a claim that it was unreported throughout the original paper.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application

Related sources S03

N10 · Were the actual comparative design, allocation and baseline balance in the isolated-deficiency population verified?

Current findings: Prospective human observation and a small comparison in a cancer population are verified, but an eligible between-group Hb design in adults with confirmed isolated deficiency and B12 deficiency excluded remains unverified. The original evidence_status records the existence of human data separately from the absence of an eligible comparison.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Material with other designs or populations does not substitute for the direct-comparison gate.
Reason for missing information: Allocation/concealment, baseline balance and a causal comparison for the direct question cannot be verified.
Required materials and conditions: Original records of selection, design, allocation/concealment, baseline status, background care and control, and denominators in an eligible comparison
Materials to obtain first: Original records of selection, design, allocation/concealment, baseline status, background care and control, and denominators in an eligible comparison
Further research: Specify an ethically permissible prospective comparison and the effect of interest, and record selection/allocation and baseline confounding.
Remaining uncertainty: Allocation/concealment, baseline balance and a causal comparison for the direct question cannot be verified.
Conditions for verification: Separate the currently known designs from the unverified status of a direct comparison in the isolated-deficiency population.
Why this condition is needed: Required to distinguish the existence of human research from a direct comparative design for the selected question.
Application exceptions: Prospective observations are also preserved. Randomized placebo comparisons are not newly designated as the sole permissible evidence for replacement treatment.
Referenced methods: M08 §8.1–8.2.3; internal application; M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed

Related sources S01 S02

N11 · Were the participant count and the number of analytical replicates in Golding's self-experiment distinguished?

Current findings: Golding is a depletion-and-repletion self-experiment involving 1 participant. The randomized count is 0 and the eligible concurrent-control count is 0; analytical replicates are not participants. The recovery record is not a between-group Hb effect.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The design and participant count are verified, but they do not provide the comparison specified by the main question.
Reason for missing information: There is no concurrent control without added folic acid or formal between-group Hb estimate.
Required materials and conditions: Original records of the self-experiment's design, participant/randomized/control counts and repeated tests
Materials to obtain first: Original records of the self-experiment's design, participant/randomized/control counts and repeated tests
Further research: In prospective data, report participants, specimens and analytical replicates separately, and specify the limitations of the comparison.
Remaining uncertainty: There is no concurrent control without added folic acid or formal between-group Hb estimate.
Conditions for verification: Link the depletion-and-recovery trajectory of one person to the implications of having no concurrent control.
Why this condition is needed: Required to avoid counting analytical replicates or specimens as new participants or independent comparisons.
Application exceptions: Recovery in 1 person is retained as information but is not converted into a between-group effect or population incidence.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.1–8.2.3; internal application; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application

Related sources S01

N12 · To what extent were Golding's Hb recovery timing and graph values read?

Current findings: Normal diet and folate supplementation resumed on study day 586; the Hb, red-cell count and hematocrit nadir was near day 588, and return to initial levels was reported by day 772. Numerical values were not reconstructed from graph heights.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The favorable recovery context and time coordinates are preserved, but they are not a controlled treatment effect or a general recovery duration.
Reason for missing information: The effect estimate cannot be reconstructed because no numerically read original Hb values, variance or control-group change are available.
Required materials and conditions: The depletion-and-repletion timeline, reported Hb trajectory and extent of reading of the original graph
Materials to obtain first: The depletion-and-repletion timeline, reported Hb trajectory and extent of reading of the original graph
Further research: Observational studies should report Hb trajectories, times of changes and conditions that changed together, and distinguish causal effects from descriptive data.
Remaining uncertainty: The effect estimate cannot be reconstructed because no numerically read original Hb values, variance or control-group change are available.
Conditions for verification: Retain the study-day coordinates and recovery narrative without turning them into a quantitative between-group comparison.
Why this condition is needed: Required to preserve favorable recovery without converting an uncontrolled trajectory into an effect estimate.
Application exceptions: The graphs are not digitized, and the Hb value at the nadir is not reconstructed.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application

Related sources S01

N13 · Were Golding's resumption of normal diet and concurrent B12 use distinguished from the contribution of folic acid?

Current findings: Golding's participant maintained methylcobalamin 1000 µg/day and monitored B12 markers. Normal diet and folate supplementation resumed together, so the before-and-after recovery is not interpreted as an isolated between-group effect of folic acid.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Cointervention records are verified, but there is no control from which to estimate the independent contribution of folic acid.
Reason for missing information: The contributions of diet, B12 and folic acid cannot be disentangled.
Required materials and conditions: Original records of diet, folate, methylcobalamin, B12 tests and times of changes
Materials to obtain first: Original records of diet, folate, methylcobalamin, B12 tests and times of changes
Further research: Record concurrent nutrients, drugs, diet and the times of changes, and separate the incremental contribution of the ingredient of interest through an appropriate comparison.
Remaining uncertainty: The contributions of diet, B12 and folic acid cannot be disentangled.
Conditions for verification: Link concurrent B12 at 1000 µg/day and resumption of diet to the context of the self-experiment.
Why this condition is needed: Required to avoid attributing simultaneous dietary changes and cointerventions to the effect of folic acid alone.
Application exceptions: B12 monitoring and methylcobalamin administration are not treated as equivalent to diagnostic exclusion.
Referenced methods: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed

Related sources S01

N14 · Is Shammo's cancer/olaparib population the same as a population with confirmed isolated folate-deficiency anemia?

Current findings: Shammo is a prospective study of patients receiving olaparib for cancer. An eligible between-group Hb result for the stratum with confirmed megaloblastic anemia and B12 deficiency excluded could not be separately verified.
Verification status: Not met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The currently verified population and outcomes do not meet the direct criteria of the question about adults with isolated deficiency.
Reason for missing information: Values from populations with other etiologies and strata that have not been separately verified cannot be used as the main effect.
Required materials and conditions: Original data on cancer/drugs, anemia/folate diagnosis, and the stratum with megaloblastic anemia and B12 deficiency excluded
Materials to obtain first: Original data on cancer/drugs, anemia/folate diagnosis, and the stratum with megaloblastic anemia and B12 deficiency excluded
Further research: Separate population strata with drug-induced causes from those with isolated deficiency, and report Hb comparisons by stratum.
Remaining uncertainty: Values from populations with other etiologies and strata that have not been separately verified cannot be used as the main effect.
Conditions for verification: Explain the differences between the olaparib-related population and the confirmed isolated-deficiency population, and the unverified status of the separately defined stratum.
Why this condition is needed: Required to avoid transferring a comparison in cancer- or drug-induced anemia to isolated nutritional deficiency.
Application exceptions: The randomized component in the related material is not disregarded; the population mismatch and the unverified effect are retained separately.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application

Related sources S02

N15 · Were the 9 enrolled participants, the 2+2 allocated participants and the 12-month completion denominator distinguished?

Current findings: Of 10 people who consented, 9 enrolled, and 4 were allocated as 2 to folic acid versus 2 to no supplementation. There were 5 nonrandomized participants, and the 5 who completed 12 months refer to the entire cohort. The fixed-time Hb analysis denominators by group remain unverified.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The overall flow is verified, but Hb analysis denominators by group and the fixed time point have not been verified.
Reason for missing information: Enrollment and completion counts cannot be reused as n for an eligible Hb result.
Required materials and conditions: Original flow records for consent, enrollment, randomization, nonrandomization, completion and Hb analysis by group
Materials to obtain first: Original flow records for consent, enrollment, randomization, nonrandomization, completion and Hb analysis by group
Further research: Report the flow of the entire cohort separately from that of the allocated subgroup, and provide analysis denominators at each Hb time point.
Remaining uncertainty: Enrollment and completion counts cannot be reused as n for an eligible Hb result.
Conditions for verification: Attribute each count to its own stage: 10 consented, 9 enrolled, 4 allocated as 2+2, 5 nonrandomized, and 5 completing 12 months in the entire cohort.
Why this condition is needed: Required to avoid using the entire cohort as the denominator for randomized Hb analyses.
Application exceptions: The total of 9 participants and the 5 completers are not the Hb analysis counts for each group. Analysis denominators absent from the original text are not filled in by arithmetic.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.1–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application

Related sources S02

N16 · To which trial do Shammo's 1 mg/day dose and folate/Hb allocation and rescue criteria belong?

Current findings: Shammo used oral folic acid at 1 mg/day. Allocation occurred at folate <7 ng/mL and Hb <12 g/dL, and the protocol specified starting rescue folate at Hb <10 g/dL regardless of allocation. This protocol is not used as universal criteria for confirming deficiency or megaloblastic anemia.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Exposure and protocol details for that oncology trial are preserved, but the regimen and analysis of rescue use for the main population remain unverified.
Reason for missing information: Actual rescue use and exposure by group are distinct from the diagnostic confirmation cutoffs for the main question.
Required materials and conditions: The original trial dose, folate/Hb allocation criteria, rescue policy and actual use by group
Materials to obtain first: The original trial dose, folate/Hb allocation criteria, rescue policy and actual use by group
Further research: Record the ethical rescue policy, actual timing of use and denominators, and specify its impact in the analysis of the effect of interest.
Remaining uncertainty: Actual rescue use and exposure by group are distinct from the diagnostic confirmation cutoffs for the main question.
Conditions for verification: Attribute oral 1 mg/day, folate <7 ng/mL and Hb <12 g/dL, and rescue at Hb <10 g/dL to the oncology trial.
Why this condition is needed: Required to avoid extending an oncology trial's protocol into general diagnostic confirmation criteria or a treatment regimen.
Application exceptions: Rescue at Hb <10 g/dL is this trial's original protocol, not a threshold for withholding treatment from patients generally.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed

Related sources S02

N17 · Were Shammo's change from the placebo plan and the actual control without supplementation distinguished?

Current findings: Shammo's initial placebo plan changed to a control without supplementation because of cost. It is a small open-label randomized component within a prospective cohort and is not presented as a randomized double-blind placebo Hb trial.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The current retained wording verifies the difference between the planned and actual control, but the full protocol, SAP and amendment history remain unverified.
Reason for missing information: A complete cross-check of the planned control against actual allocation and analysis could not be performed.
Required materials and conditions: The original plan, reasons for changes, open-label/blinding status, actual control without supplementation and analysis documents
Materials to obtain first: The original plan, reasons for changes, open-label/blinding status, actual control without supplementation and analysis documents
Further research: Transparently report the plan, reasons for changes, actual control, blinding and Hb analysis of interest.
Remaining uncertainty: A complete cross-check of the planned control against actual allocation and analysis could not be performed.
Conditions for verification: Link the abandonment of placebo and the comparison without supplementation to the actual design, and distinguish the amendment history.
Why this condition is needed: Required to avoid presenting the initially planned placebo as an actual blinded trial.
Application exceptions: The cost-related change is recorded, but the lack of an obtained protocol is not converted into a confirmed finding of selective reporting.
Referenced methods: M08 §8.1–8.2.3; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed

Related sources S02 S10

N18 · Were the phase IV and phase II/single-arm labels recorded in Shammo's original text preserved without arbitrarily harmonizing them?

Current findings: The retained citation records a discrepancy between the phase IV narrative on PDF p.1/3 and the phase II/single-arm template on p.2. The small randomized component actually linked in the record is retained, and the phase labels were not arbitrarily corrected.
Verification status: Conflicting information
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: This is an explicit conflict in phase/design wording within the same report, not merely a difference between analyses.
Reason for missing information: The correct phase, the reason for the template change and any original correction currently remain unverified.
Required materials and conditions: The relevant original pages, design wording, corrections or author explanations
Materials to obtain first: The relevant original pages, design wording, corrections or author explanations
Further research: Align design labels with the actual allocation component, and record an original explanation or correction as a separate event when available.
Remaining uncertainty: The correct phase, the reason for the template change and any original correction currently remain unverified.
Conditions for verification: Preserve the discrepancy between p.1/3 phase IV and the p.2 phase II/single-arm template, together with their locations.
Why this condition is needed: Required to avoid inferring one actual phase from inconsistent design labels within the same report.
Application exceptions: The wording conflict is reported in the currently retained citation; the original full text was not independently rechecked in this review.
Referenced methods: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.1–8.2.3; internal application

Related sources S02

N19 · Were Shammo's interpretation of secondary Hb results and olaparib dose reduction kept from being converted into a between-group effect?

Current findings: Shammo's primary question concerns the frequency and timing of folate deficiency, and Hb is secondary. Olaparib dose reduction in controls is asymmetric, and a formal between-group Hb estimate for the fixed population stratum remains unverified. Recovery of deficient folate concentrations and the authors' interpretation are not converted into equivalence.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The endpoint hierarchy and changes in background care are preserved, but the direct Hb effect of interest could not be verified.
Reason for missing information: There are no Hb values with which to distinguish the contributions of analysis, adjustment and the control to the main question.
Required materials and conditions: Secondary Hb results, medication changes by group, formal Hb estimates/variance/time points and the original protocol
Materials to obtain first: Secondary Hb results, medication changes by group, formal Hb estimates/variance/time points and the original protocol
Further research: Predefine Hb as the outcome of interest, record background medication and rescue treatment, and report adjusted and sensitivity analyses for the comparison of interest.
Remaining uncertainty: There are no Hb values with which to distinguish the contributions of analysis, adjustment and the control to the main question.
Conditions for verification: Attribute the primary frequency/timing of folate deficiency, secondary Hb and olaparib dose reduction in controls to their respective roles.
Why this condition is needed: Required to avoid turning folate recovery, author narratives and asymmetric medication changes into a formal Hb effect.
Application exceptions: The authors' interpretation of Hb is preserved, but nonsignificance or unverified quantitative information is not used as equivalence or an effect of 0.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application

Related sources S02

N20 · How were Clarke's case and Sheehy's tropical-sprue material preserved?

Current findings: Clarke is a 1-person case involving alcohol, liver disease and bleeding. Detailed transfusion counts, dose and a causal Hb effect remain unverified within the retained scope. Sheehy is a historical dose-titration study in tropical-sprue malabsorption; matching B12 exclusion and an Hb contrast for oral folic acid versus no added folic acid remain unverified.
Verification status: Not met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The current populations and designs do not match the comparison of folic acid alone in adults with isolated deficiency. Recovery context and access limitations are retained.
Reason for missing information: Hematologic recovery from other etiologies cannot be transferred into an Hb estimate for the direct comparison.
Required materials and conditions: Case etiology, cointerventions/transfusion, administration/control, B12 exclusion, Hb values and the actual extent of access
Materials to obtain first: Case etiology, cointerventions/transfusion, administration/control, B12 exclusion, Hb values and the actual extent of access
Further research: Report etiology, concurrent treatment, tests and denominators separately, and evaluate them through a comparison appropriate to that population's question.
Remaining uncertainty: Hematologic recovery from other etiologies cannot be transferred into an Hb estimate for the direct comparison.
Conditions for verification: Specify the differences between Clarke's 1-person case with mixed etiologies and Sheehy's malabsorption/dose-titration setting.
Why this condition is needed: Required to preserve related hematologic recovery without counting it as replication in isolated deficiency.
Application exceptions: Limited full-text access is not expanded into a claim of nonreporting in the original text or absence of research in this review.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed

Related sources S03 S04

N21 · Does Obeid's folate-marker study in nonpregnant women provide an Hb treatment result in confirmed anemia?

Current findings: Obeid is an index-level lead identifying a folate-biomarker supplementation study in nonpregnant women. It was not used as a direct Hb effect of treatment for confirmed megaloblastic anemia, and the current n record is empty.
Verification status: Not met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The currently verified population/endpoints differ from the Hb comparison in confirmed anemia specified by the main question.
Reason for missing information: Improved markers in people without anemia are not direct evidence of a between-group Hb change.
Required materials and conditions: Actual anemia diagnosis, baseline status, Hb outcomes, folate markers and the location of the selection information
Materials to obtain first: Actual anemia diagnosis, baseline status, Hb outcomes, folate markers and the location of the selection information
Further research: Separate baseline anemia and deficiency from outcomes, and provide a direct Hb comparison when the question concerns Hb treatment.
Remaining uncertainty: Improved markers in people without anemia are not direct evidence of a between-group Hb change.
Conditions for verification: Record the difference between biomarker supplementation material in people without anemia and the treatment question in confirmed megaloblastic anemia.
Why this condition is needed: Required to avoid inferring a treatment effect solely from the shared characteristic of being nonpregnant or from folate recovery.
Application exceptions: An exclusion recorded at index level is not converted into a quality review of the entire original full text or a finding of no effect.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim

Related sources S06

N22 · Can Nozari's combined B12+folic acid intervention in MS be separated into an effect of folic acid alone?

Current findings: Nozari is a comparison adding B12 and folic acid together in an MS population. It does not provide a between-group Hb result for folic acid as the sole addition in adults with isolated deficiency, and n remains unverified within the index-level access scope.
Verification status: Not met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The population and intervention differ from the main question, and the contribution of folic acid alone cannot be isolated.
Reason for missing information: Results from a combination intervention and a different disease cannot be used as the selected ingredient's Hb effect.
Required materials and conditions: The MS population, B12/folic acid interventions by group, Hb/anemia/quality-of-life outcomes and a contrast with a sole added ingredient
Materials to obtain first: The MS population, B12/folic acid interventions by group, Hb/anemia/quality-of-life outcomes and a contrast with a sole added ingredient
Further research: If the question concerns each ingredient's contribution, design a direct contrast with matched background care and separate outcomes by disease.
Remaining uncertainty: Results from a combination intervention and a different disease cannot be used as the selected ingredient's Hb effect.
Conditions for verification: Link MS and the addition of two active ingredients to their differences from the main population/intervention.
Why this condition is needed: Required to avoid attributing combination results to folic acid alone when both the population and the added active ingredients differ.
Application exceptions: The favorable context of the combination data is preserved, and effects of individual ingredients are not arbitrarily disentangled.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application

Related sources S07

N23 · Were the pregnancy review and trials from historical record 121 kept from being counted as independent replications of replacement treatment in adults?

Current findings: S13 is the URL/citation of a pregnancy review inherited from the original 121. Pregnancy-prevention results and the historical combined-claim page were not counted as replications of deficiency treatment in nonpregnant people, and the original file was not reopened in this review.
Verification status: Not met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The population and prevention/treatment boundary differ, so the criteria for direct treatment replication are not met.
Reason for missing information: Review counts, included-trial counts and participant counts are not summed for the main question.
Required materials and conditions: The actual populations and prevention/treatment questions of the review/included trials, and links to original data
Materials to obtain first: The actual populations and prevention/treatment questions of the review/included trials, and links to original data
Further research: Link included trials to unique study families and their actual populations, interventions and outcomes, then separately review only material relevant to the question.
Remaining uncertainty: Review counts, included-trial counts and participant counts are not summed for the main question.
Conditions for verification: Distinguish a pregnancy-prevention review from Hb treatment in nonpregnant people with isolated deficiency, and do not infer the number of direct replications.
Why this condition is needed: Required to avoid double-counting a historical combined-claim page and trials included in a review as replications of the new isolated-deficiency treatment question.
Application exceptions: The original file for historical record 121 was not read in this review; only the reused citation record in the current 3108 was read.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application

Related sources S13

N24 · Were the direct Hb difference in change, adjusted difference in final values, and SD/SE, CI and P verified?

Current findings: The fixed question's between-group Hb difference in change, adjusted difference in final values, variance, CI, P and analysis n by group remain unverified. The original calculation fields mean_changes, sd_changes, difference, interval and n are preserved as null.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The inputs and estimates needed for a quantitative direct comparison are unavailable, so no interval could be verified for interpretation.
Reason for missing information: Empty values are distinct from an effect of 0, sufficient precision or nonsignificance. No new effect estimate or NNT is calculated.
Required materials and conditions: Original tables of Hb values/changes, units, n and SD/SE for each eligible group, the estimation model, CI and P
Materials to obtain first: Original tables of Hb values/changes, units, n and SD/SE for each eligible group, the estimation model, CI and P
Further research: Provide group-specific outcomes and variance, and the estimate and CI for the effect of interest; explain change/final-value analyses and adjustment variables.
Remaining uncertainty: Empty values are distinct from an effect of 0, sufficient precision or nonsignificance. No new effect estimate or NNT is calculated.
Conditions for verification: Separate between-group change from the adjusted difference in final values, and specify that variance, intervals and tests remain unverified.
Why this condition is needed: Required to avoid filling absent direct values with 0 or reconstructing them from graphs or other markers.
Application exceptions: Keep the variance type and CI unverified when they are unverified, and do not determine precision from sample size alone.
Referenced methods: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application

Related sources

N25 · Were ITT/PP, completion/analysis denominators, missing data and Hb analysis in the main comparison verified?

Current findings: Eligible analysis and completion denominators by group, ITT/PP and missing-data handling for the main question remain unverified. Shammo's 5 completers at 12 months across the entire cohort were not used as Hb completion n for the two arms.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Eligible Hb analysis information is unavailable, and the flow of a related cohort does not substitute for the main analysis.
Reason for missing information: Differences in the effect of interest arising from denominators, missing data and deviations cannot be assessed.
Required materials and conditions: Flow, Hb measurement/analysis n, ITT/PP, reasons for and handling of missing data, and sensitivity analyses for each eligible group
Materials to obtain first: Flow, Hb measurement/analysis n, ITT/PP, reasons for and handling of missing data, and sensitivity analyses for each eligible group
Further research: Define the effect of interest and analysis population in advance, and report how missing Hb data, dropout and rescue treatment were handled by group, together with sensitivity analyses.
Remaining uncertainty: Differences in the effect of interest arising from denominators, missing data and deviations cannot be assessed.
Conditions for verification: Separate allocation, completion and analysis, and link the selected effect of interest to the unverified status of the actual analysis.
Why this condition is needed: Required to avoid turning enrollment, allocation or before-and-after measurement counts into actual Hb analysis denominators.
Application exceptions: Unverified analysis details are not converted into randomization failure, confirmed selective reporting or 0 missing observations.
Referenced methods: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application

Related sources S02 S10

N26 · Were the clinical importance of Hb and questions about symptoms, transfusion and survival distinguished?

Current findings: A clinically important Hb criterion for the main question remains unverified. Hb concentration is laboratory surrogate endpoint S and is not automatically extended to direct effects on fatigue, transfusion, correction rates or survival.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The magnitude of clinical benefit cannot be determined because importance criteria and direct event outcomes have not been verified.
Reason for missing information: The gap in the Hb question is not expanded into absence of all patient benefit.
Required materials and conditions: A justified criterion for an important Hb difference in the relevant population, and direct outcomes for symptoms, transfusion and quality of life/survival
Materials to obtain first: A justified criterion for an important Hb difference in the relevant population, and direct outcomes for symptoms, transfusion and quality of life/survival
Further research: Justify an important Hb difference for the population and context, and measure patient-centered events as separate outcomes.
Remaining uncertainty: The gap in the Hb question is not expanded into absence of all patient benefit.
Conditions for verification: Distinguish the degree to which an Hb importance criterion is verified from the degree to which separate event evidence is verified.
Why this condition is needed: Required to avoid extending the clinical scope of treatment benefit solely from a laboratory change.
Application exceptions: When the original question concerns Hb values, survival trials are not imposed as mandatory. No universal MCID, minimum participant count or duration is newly invented.
Referenced methods: M15 §15.3.1–15.3.3; internal application; M03 §3.2.4; internally defined boundaries for extending the claim; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed

Related sources

N27 · To what extent were each report's family and funding/product/conflict-of-interest information verified?

Current findings: S02 and S10 are the paper and registration for NCT04024254. S11 is product labeling, and S13 is a reused citation of a historical review. Funding in evidence only refers to a separate evidence_appraisal.json, and citation only records the locations of COI/funding sections, so the actual disclosures are not described as verified in this review.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Verified families/roles were linked, but the detailed original values for funding, products and author disclosures are absent from the current stored summaries.
Reason for missing information: The unique direct-trial count, total participant count and independent support remain unverified. The historical separate appraisal file was not read.
Required materials and conditions: Unique-study/reused-citation relationships and original wording on research funding, product provision and author disclosures
Materials to obtain first: Unique-study/reused-citation relationships and original wording on research funding, product provision and author disclosures
Further research: Disclose family relationships, overlapping reports, funding and product roles, and verify independent direct comparisons through actual links.
Remaining uncertainty: The unique direct-trial count, total participant count and independent support remain unverified. The historical separate appraisal file was not read.
Conditions for verification: Link evidence study_id, shared registration and material roles, and leave funding unverified where the original text is unavailable.
Why this condition is needed: Required to avoid inferring independent replication or verified funding solely from 13 reports and location references.
Application exceptions: Unverified conflicts of interest are not treated as independent support, and product documents are identified as manufacturer material.
Referenced methods: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items

Related sources S01 S02 S10 S11 S13

N28 · Were the registry shell and the original protocol/SAP, amendment history and current status distinguished?

Current findings: NCT04024254 is a registry-shell record linked to S02 Methods. Registration timing, amendments and current status were not independently certified in the historical review, and history/results/protocol contents are retained as not accessed.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The registration identity was linked, but the endpoints, time points, SAP and cross-check of the full history remain unverified.
Reason for missing information: The identifier and link alone do not establish preregistration or current recruitment/completion status.
Required materials and conditions: The original NCT04024254 registration/history, protocol, SAP, Hb hierarchy/time points and reasons for amendments
Materials to obtain first: The original NCT04024254 registration/history, protocol, SAP, Hb hierarchy/time points and reasons for amendments
Further research: Link the Hb outcome, time point and analysis of interest, and actual amendments, to public records and cross-check them against actual reporting.
Remaining uncertainty: The identifier and link alone do not establish preregistration or current recruitment/completion status.
Conditions for verification: Separate the retained identifier linkage from unverified registration timing, history and current status.
Why this condition is needed: Required to avoid turning the existence of a registration number into proof of preregistration, endpoint agreement or current completion.
Application exceptions: Limited access to the original protocol does not establish nonregistration or selective reporting. It is also not a failed access attempt in this review.
Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application

Related sources S02 S10

N29 · Were BSH's replacement notice and the unverified NICE details distinguished?

Current findings: The retained record states that the BSH page identifies the document dated 2014-06-18 and, in its 2024-11-20 update, announces replacement of B12 guidance by NICE NG239 dated 2024-03-06. Exact NICE B12/MMA cutoffs and treatment instructions could not be extracted.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The replacement identity/version notice is preserved, but the original diagnostic details have not been verified.
Reason for missing information: The currency of the guideline as a whole, diagnostic cutoffs or individual treatment instructions are not newly established.
Required materials and conditions: BSH version/update notices, the identity of NICE NG239 and the actual original diagnostic/treatment recommendations
Materials to obtain first: BSH version/update notices, the identity of NICE NG239 and the actual original diagnostic/treatment recommendations
Further research: When updating diagnostic/safety criteria, cross-check the actual original recommendations, version, applicable population and reasons for changes.
Remaining uncertainty: The currency of the guideline as a whole, diagnostic cutoffs or individual treatment instructions are not newly established.
Conditions for verification: Separate the 2024 replacement notice for the 2014 document from the unverified scope of the original recommendations.
Why this condition is needed: Required to avoid presenting an old guideline as unchanged current guidance or filling in diagnostic criteria that have not been read.
Application exceptions: The original NICE recommendations were not read in this review, and the earlier failure to access the body text is retained as a historical record.
Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied

Related sources S08 S09

N30 · Was the Swiss HTA's evidence on testing utility kept from being transferred into a claim of no effect of folic acid treatment?

Current findings: The Swiss 2023 HTA evaluates the clinical utility of folate testing itself. Gaps in testing evidence were not repurposed as ineffectiveness of replacement treatment or a worldwide absence of treatment research. Only selected narrative sections were read at that time; numerical appendices and cutoffs could not be extracted.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The difference between questions and the reading limitations in the current stored material were linked. This does not verify a treatment effect.
Reason for missing information: This HTA does not provide a direct between-group Hb result for the selected question.
Required materials and conditions: The HTA's question about the clinical utility of testing, original sections/pages and distinction from the treatment context
Materials to obtain first: The HTA's question about the clinical utility of testing, original sections/pages and distinction from the treatment context
Further research: Evaluate patient outcomes and treatment comparisons for a testing strategy separately from direct replacement-treatment effects as distinct research questions.
Remaining uncertainty: This HTA does not provide a direct between-group Hb result for the selected question.
Conditions for verification: Separate the question of folate testing from the question of Hb treatment in isolated deficiency.
Why this condition is needed: Required to avoid using a lack of evidence for the testing question to claim that replacement-treatment research or all human research is absent.
Application exceptions: Historical reading of some HTA narrative does not verify values in the original appendices or diagnostic cutoffs.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed

Related sources S12

N31 · Were recognized replacement treatment and the dose on the S11 label distinguished from a direct comparative effect?

Current findings: S11 describes single-ingredient oral folic acid tablets and the indication of folate-deficient megaloblastic anemia. The adult regimen of 5 mg/day for 4 months belongs to that product's labeling; it is not the regimen of an eligible trial in this review, a placebo-controlled effect estimate or an individual instruction.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The official product's treatment context is a verified retained record, but the quantitative effect in the main comparison remains unverified.
Reason for missing information: Authorized labeling cannot be used as a between-group Hb estimate or as proof of identity with an eligible trial.
Required materials and conditions: S11 product identity, indication, labeled dose/duration and version, and the identity of an eligible trial
Materials to obtain first: S11 product identity, indication, labeled dose/duration and version, and the identity of an eligible trial
Further research: Use labeling as treatment context, and report the actual comparison, exposure and Hb outcomes for the question of interest separately.
Remaining uncertainty: Authorized labeling cannot be used as a between-group Hb estimate or as proof of identity with an eligible trial.
Conditions for verification: Retain recognized replacement treatment and product labeling, while separating them from verified between-group results and regimens.
Why this condition is needed: Required to avoid turning an authorized indication or 5 mg/4 months into a trial effect estimate or individual dosing instructions.
Application exceptions: An unverified direct effect is not interpreted as recognized treatment being unnecessary or as advice to delay treatment.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

Related sources S11

N32 · Were the original nonapplication of RE, allowance for prospective observation and prohibition on withholding treatment retained unchanged?

Current findings: The original review acknowledged objective diagnosis, a direct replacement mechanism and prospective human observation. RE was not applied because proof of the historical absence of placebo trials and quantitative evidence of untreated mortality/irreversible harm were not obtained. The allowance for prospective observation is not changed into a requirement for a placebo RCT.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The original RE logic and the boundaries for presenting treatment ethics were preserved accurately. RE was not newly adjudicated or established as met.
Reason for missing information: The missing gates were not established within the original verification scope; they are not a reason to delay recognized treatment.
Required materials and conditions: The original reasons for the RE decision, objective diagnosis/replacement mechanism, prospective observation and the extent of verification of the five gates at that time
Materials to obtain first: The original reasons for the RE decision, objective diagnosis/replacement mechanism, prospective observation and the extent of verification of the five gates at that time
Further research: First define an ethical comparison appropriate to this question and the effect of interest, then evaluate actual data; do not recommend a no-treatment experiment.
Remaining uncertainty: The missing gates were not established within the original verification scope; they are not a reason to delay recognized treatment.
Conditions for verification: Preserve the allowance for prospective observation and the gates that were not established, and record the original RE_eligible=false unchanged.
Why this condition is needed: Required to avoid turning the exception logic of the current original verdict into a new score, a mandatory placebo requirement or treatment delay.
Application exceptions: No new determination is made about whether RE is met or whether no treatment is ethically permissible. There is no assumption that withholding treatment is acceptable.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M08 §8.1–8.2.3; internal application; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

Related sources S01 S02 S11 S12

N33 · Was improvement in Hb distinguished from resolution of neurological problems due to B12 deficiency?

Current findings: S11 warns against treating B12 deficiency/undiagnosed anemia with folic acid alone, because folic acid can improve the hematologic findings of B12 deficiency and delay recognition of neurological damage. Hb recovery is not evidence that the B12 problem has been resolved.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The label warning is preserved, but the frequency of neurological harm in the selected population and at the selected dose remains unverified.
Reason for missing information: Incidence, latency, discontinuation/recovery, exposure amount and denominators could not be verified.
Required materials and conditions: S11 contraindications and precautions for B12 deficiency/undiagnosed anemia, and actual neurological-harm definitions and exposure/denominator data
Materials to obtain first: S11 contraindications and precautions for B12 deficiency/undiagnosed anemia, and actual neurological-harm definitions and exposure/denominator data
Further research: Record B12 exclusion and neurological observations, and separately collect actual harm definitions, timing, exposure and denominators.
Remaining uncertainty: Incidence, latency, discontinuation/recovery, exposure amount and denominators could not be verified.
Conditions for verification: Record warnings about masking B12 findings and delayed recognition separately from Hb recovery and unverified frequency.
Why this condition is needed: Required to avoid implying that hematologic improvement means resolution of B12 deficiency or neurological safety.
Application exceptions: The official warning is product context and does not determine incidence or individual risk in the isolated-deficiency population.
Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied

Related sources S11

N34 · Were gastrointestinal and allergic reactions and interactions distinguished from actual event denominators in the eligible population?

Current findings: The context of gastrointestinal and allergic adverse reactions and interactions with antiepileptics and methotrexate in the product label was preserved. This is not AE/SAE, discontinuation-count, denominator or incidence data for the main isolated-deficiency population.
Verification status: Partly verified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Warning/reaction context is available, but comparative frequencies and the extent of data collection for the same population and exposure remain unverified.
Reason for missing information: Event rates, safety equivalence and absence of serious harm cannot be verified.
Required materials and conditions: Original data on AE/SAE, discontinuation, exposure/duration, collection methods, people with events/event counts and concomitant drugs for each eligible group
Materials to obtain first: Original data on AE/SAE, discontinuation, exposure/duration, collection methods, people with events/event counts and concomitant drugs for each eligible group
Further research: Report harm definitions, systematic collection, people/event counts, exposure time and denominators by group, and analyze drug interactions in their relevant context.
Remaining uncertainty: Event rates, safety equivalence and absence of serious harm cannot be verified.
Conditions for verification: Distinguish S11's gastrointestinal/allergic and antiepileptic/methotrexate context from the gap in direct event rates.
Why this condition is needed: Required to avoid turning a product's reaction list into comparative event rates or absence of risk in the main population.
Application exceptions: The statuses Not read and Unverified are not converted into 0 people with adverse reactions/SAE/discontinuation.
Referenced methods: M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application

Related sources S05 S11

N35 · Can safety/efficacy be extended to high doses, long-term use, liver or kidney disease, cancer, malabsorption, pregnancy/lactation and children?

Current findings: Applicability differs for long-term high doses, liver or kidney disease, malabsorption, a history of cancer, pregnancy/lactation and children. Their efficacy, incidence or safety is not established from the current main question or product labeling.
Verification status: Unverified
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Direct material for each extension has not currently been verified, and the populations also differ from the original question.
Reason for missing information: Unverified does not mean no risk or no effect, and it does not certify extended applicability.
Required materials and conditions: Actual exposure/effect by population, dose and duration, rare/long-term harms, and drug/underlying-disease data
Materials to obtain first: Actual exposure/effect by population, dose and duration, rare/long-term harms, and drug/underlying-disease data
Further research: For each extension question, separately collect appropriate design, exposure, long-term follow-up and outcomes in vulnerable populations.
Remaining uncertainty: Unverified does not mean no risk or no effect, and it does not certify extended applicability.
Conditions for verification: Record the question about nonpregnant adults with isolated deficiency separately from the unverified scope for each special population.
Why this condition is needed: Required to avoid extending related product context or brief recovery to safety/efficacy in all populations.
Application exceptions: Studies in every special population are not imposed as mandatory for the original Hb question, and individual dosing instructions are not provided.
Referenced methods: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied; M03 §3.2.1; detailed population criteria are internally designed

Related sources S11

N36 · Was historical access for the 13 bibliographic records distinguished from reading local summaries in this review?

Current findings: In this review, the Korean text/structure of the current stored summaries and 13 bibliographic records were read. Historical levels such as Golding HTML, parsed Shammo text and official labeling/HTA are retained reports; no clinical full text was read in this review. Report-specific access dates are absent and left empty, while the original review date is separately recorded as 2026-09-15.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: Actual summary reading was separated from current nonreading and historical access by material type. This does not mean full-text verification was completed.
Reason for missing information: The original clinical files, registrations and full official web texts have not currently been obtained, and the historical ZIP/separate logs were not read either.
Required materials and conditions: Material type, URL, historical access_level/flag, dates and original locations for each report, and exact current stored-summary anchors
Materials to obtain first: Material type, URL, historical access_level/flag, dates and original locations for each report, and exact current stored-summary anchors
Further research: During any authorized subsequent material check, record original locations, material type, dates, acquisition/reading and access failures separately.
Remaining uncertainty: The original clinical files, registrations and full official web texts have not currently been obtained, and the historical ZIP/separate logs were not read either.
Conditions for verification: Separate actual reading, acquisition and access status by material type into current and historical records, and leave records without access dates empty.
Why this condition is needed: Required to avoid upgrading original full-text access flags and links into full-text reading in this review.
Application exceptions: Access to all external material is currently unattempted, and none of it has been read in this review; historical failures are not presented as failures in this review.
Referenced methods: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

Related sources S01 S02 S03 S04 S05 S06 S07 S08 S09 S10 S11 S12 S13

N37 · Were the original ?/empty values, axes, safety and publication records distinguished from the new criteria statuses?

Current findings: The original grade is ?, score is null, safety is Caution, and the five axes beyond B/S are null. The existence of human research is distinguished from unverified directly eligible results. The original server_deployed=true, server_write=false and 2026-09-15 publication metadata are historical records; the new table has not been deployed.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The original verdict and scope metadata were preserved, and no new score or efficacy judgment was assigned to criteria statuses.
Reason for missing information: Criteria checks, technical checks passed and original server flags are not independent clinical certification or evidence of current incorporation into the website.
Required materials and conditions: Original grade/score/axes, calculation, evidence_status, publication/server metadata and the scope of the new table
Materials to obtain first: Original grade/score/axes, calculation, evidence_status, publication/server metadata and the scope of the new table
Further research: Separate material/criteria updates from the original clinical verdict and events of public release, preserving the original text before and after changes.
Remaining uncertainty: Criteria checks, technical checks passed and original server flags are not independent clinical certification or evidence of current incorporation into the website.
Conditions for verification: Preserve the original verdict values byte for byte, and separate them from criteria statuses and the fact that this public version has not been deployed.
Why this condition is needed: Required to avoid carrying over the original score or internal deployment metadata as new efficacy, safety or completed public website publication.
Application exceptions: The original first_published_at is the content baseline date; server_deployed and server_write=false are retained records.
Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design

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N38 · What would actually update the gaps within the retained search scope of 2026-09-15?

Current findings: The original cutoff date is 2026-09-15, and the search was limited, including selected full texts, abstracts and inaccessible material. The retained policy is to append to the history under the same ID/URL when new matching Hb results, original texts/protocols, corrections/retractions, numerical/classification errors or B12 diagnostic/safety changes are actually verified.
Verification status: Met
Materials actually read: Summary read: the exact locations in the current locally stored summaries were read. Access to the external material was not attempted, and that material was not read in this review.
Why unverified: The scope of the original gaps was distinguished from update events. This does not mean new material has been verified or the search is complete.
Reason for missing information: The referenced historical search/numerical/appraisal logs and ZIP were not opened in this review, and the latest external status remains unverified.
Required materials and conditions: New direct Hb results, actual original texts/protocols, corrections/retractions, and evidence of numerical, classification, diagnostic and safety changes
Materials to obtain first: New direct Hb results, actual original texts/protocols, corrections/retractions, and evidence of numerical, classification, diagnostic and safety changes
Further research: Subsequent updates should establish material identity, dates, original locations and reading scope, and cross-check the question of interest together with the original results and gaps.
Remaining uncertainty: The referenced historical search/numerical/appraisal logs and ZIP were not opened in this review, and the latest external status remains unverified.
Conditions for verification: Record the original cutoff date, incompleteness, unchanged ID/URL, reasons for changes and re-review of linked rows.
Why this condition is needed: Required to avoid turning a limited current value into an up-to-date exhaustive search or a claim of permanent absence.
Application exceptions: This is not a new search, correction/retraction lookup, calculation or reassessment. Revision of criteria and addition of evidence are separate events.
Referenced methods: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application

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