# Folic acid, single added active ingredient by mouth × Hemoglobin increase in confirmed folate-deficient megaloblastic anemia Verdict 3108 · Evidence Check Stored-material review date: 2026-10-05 Original evidence date: 2026-09-15 Review-criteria version: NGM-v3108-ISOLATED-FOLATE-ANEMIA-HB-1.1 Public page/material preparation date: 2026-11-05 Clinical papers were not read directly; existing review summaries were checked. No new clinical-literature search was performed. Unverified does not mean that research is absent or that there is no effect. ## Assessment scope - 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 ## Checklist items ### N01 · Which population with deficiency, oral folic acid comparison and Hb outcome does this table address? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The actual formulation, dose, duration and between-group results of an eligible comparison remain separately unverified. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Test values, thresholds and the population stratum with B12 deficiency excluded cannot be linked to a direct Hb comparison. - 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? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The direct Hb effect in this population stratum and effects in groups with other etiologies are not interchangeable. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Official product labeling cannot be carried over as proof of identity with the actual trial product. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The optimal dose, duration, dosing schedule or equivalence of other routes cannot be determined. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The extent to which concurrent diet, drugs, transfusion and rescue treatment contributed to the outcome remains unverified. - 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? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The original Hb values, changes, adjustment status and units in a direct comparison remain unverified. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: No new treatment duration or mean recovery time is calculated from the observational coordinates. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Measurement limitations and other factors affecting Hb change in each group of the main comparison cannot be assessed quantitatively. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Allocation/concealment, baseline balance and a causal comparison for the direct question cannot be verified. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: There is no concurrent control without added folic acid or formal between-group Hb estimate. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The effect estimate cannot be reconstructed because no numerically read original Hb values, variance or control-group change are available. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The contributions of diet, B12 and folic acid cannot be disentangled. - 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? Verification status: Not met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Values from populations with other etiologies and strata that have not been separately verified cannot be used as the main effect. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Enrollment and completion counts cannot be reused as n for an eligible Hb result. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Actual rescue use and exposure by group are distinct from the diagnostic confirmation cutoffs for the main question. - Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: A complete cross-check of the planned control against actual allocation and analysis could not be performed. - 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? Verification status: Conflicting information Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The correct phase, the reason for the template change and any original correction currently remain unverified. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: There are no Hb values with which to distinguish the contributions of analysis, adjustment and the control to the main question. - 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? Verification status: Not met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Hematologic recovery from other etiologies cannot be transferred into an Hb estimate for the direct comparison. - 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? Verification status: Not met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Improved markers in people without anemia are not direct evidence of a between-group Hb change. - 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? Verification status: Not met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Results from a combination intervention and a different disease cannot be used as the selected ingredient's Hb effect. - 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? Verification status: Not met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Review counts, included-trial counts and participant counts are not summed for the main 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 - Related sources: S13 ### N24 · Were the direct Hb difference in change, adjusted difference in final values, and SD/SE, CI and P verified? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Empty values are distinct from an effect of 0, sufficient precision or nonsignificance. No new effect estimate or NNT is calculated. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Differences in the effect of interest arising from denominators, missing data and deviations cannot be assessed. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The gap in the Hb question is not expanded into absence of all patient benefit. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The unique direct-trial count, total participant count and independent support remain unverified. The historical separate appraisal file was not read. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The identifier and link alone do not establish preregistration or current recruitment/completion status. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The currency of the guideline as a whole, diagnostic cutoffs or individual treatment instructions are not newly established. - 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? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: This HTA does not provide a direct between-group Hb result for the selected question. - Referenced methods: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.4, 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Authorized labeling cannot be used as a between-group Hb estimate or as proof of identity with an eligible trial. - 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? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The missing gates were not established within the original verification scope; they are not a reason to delay recognized treatment. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Incidence, latency, discontinuation/recovery, exposure amount and denominators could not be verified. - 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? Verification status: Partly verified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Event rates, safety equivalence and absence of serious harm cannot be verified. - 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? Verification status: Unverified Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Unverified does not mean no risk or no effect, and it does not certify extended applicability. - 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? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - 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. - 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? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: Criteria checks, technical checks passed and original server flags are not independent clinical certification or evidence of current incorporation into the website. - 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 - Related sources: ### N38 · What would actually update the gaps within the retained search scope of 2026-09-15? Verification status: Met Reading scope: 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. - 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. - 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. - 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. - Remaining uncertainty: The referenced historical search/numerical/appraisal logs and ZIP were not opened in this review, and the latest external status remains unverified. - 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 - Related sources: ## Evidence and sources ### S01 Golding 2014: Severe experimental folate deficiency in a human subject [Source](https://link.springer.com/article/10.1186/2193-1801-3-442) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full text of the paper | 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](https://academic.oup.com/oncolo/article-pdf/30/10/oyaf321/64417912/oyaf321.pdf) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full text of the paper | 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](https://pubmed.ncbi.nlm.nih.gov/22791479/) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full bibliographic/abstract web document | 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 | 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](https://pubmed.ncbi.nlm.nih.gov/13911562/) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full bibliographic/abstract web document | 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 | 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](https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official web document | 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](https://pmc.ncbi.nlm.nih.gov/articles/PMC6060806/) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full text of the paper | 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](https://pmc.ncbi.nlm.nih.gov/articles/PMC6355946/) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full text of the paper | 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](https://b-s-h.org.uk/guidelines/guidelines/diagnosis-of-b12-and-folate-deficiency) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official web document | 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](https://www.nice.org.uk/guidance/ng239/chapter/Recommendations) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official web document | 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](https://clinicaltrials.gov/study/NCT04024254) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full registry web document | 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 | 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](https://www.medicines.org.uk/emc/product/14604/smpc) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official web document | 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](https://www.bag.admin.ch/dam/de/sd-web/QuwyTqPLhnpP/h0041folt-hta-report.pdf) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full official HTA report | 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](https://pubmed.ncbi.nlm.nih.gov/23543547/) 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 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. 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. | Material | Public availability | Access status | Actually read | Notes | |---|---|---|---|---| | Full bibliographic/abstract web document | 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 | 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. | ## Review criteria and methods These are Chamgap's own application conditions, informed by the relevant sections of official methodological guidance. They do not constitute official assessment-tool certification or a new efficacy score. - M03 [Cochrane Handbook 6.5 (2024), chapter updated 2023-08](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03) · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13 · Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention. · 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](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04) · §4.5, §4.6.1–4.6.3, MECIR C42 · Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported. · 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](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08) · §8.1–8.2.3, Table 8.2.a · Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting. · 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](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15) · §15.2.4, §15.3.1–15.3.3 · Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision. · 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](https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19) · §19.1.2, §19.2.1–19.2.4 · Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence. · 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/materials 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. ## Material-specific source addresses - [S01-M1 · Full text of the paper](https://link.springer.com/article/10.1186/2193-1801-3-442) - [S02-M1 · Full text of the paper](https://academic.oup.com/oncolo/article-pdf/30/10/oyaf321/64417912/oyaf321.pdf) - [S03-M1 · Full bibliographic/abstract web document](https://pubmed.ncbi.nlm.nih.gov/22791479/) - S03-M2 · Full text of the paper: Material URL unverified; external material unread. - [S04-M1 · Full bibliographic/abstract web document](https://pubmed.ncbi.nlm.nih.gov/13911562/) - S04-M2 · Full text of the paper: Material URL unverified; external material unread. - [S05-M1 · Full official web document](https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/) - [S06-M1 · Full text of the paper](https://pmc.ncbi.nlm.nih.gov/articles/PMC6060806/) - [S07-M1 · Full text of the paper](https://pmc.ncbi.nlm.nih.gov/articles/PMC6355946/) - [S08-M1 · Full official web document](https://b-s-h.org.uk/guidelines/guidelines/diagnosis-of-b12-and-folate-deficiency) - [S09-M1 · Full official web document](https://www.nice.org.uk/guidance/ng239/chapter/Recommendations) - [S10-M1 · Full registry web document](https://clinicaltrials.gov/study/NCT04024254) - S10-M2 · Full study protocol and analysis plan: Material URL unverified; external material unread. - [S11-M1 · Full official web document](https://www.medicines.org.uk/emc/product/14604/smpc) - [S12-M1 · Full official HTA report](https://www.bag.admin.ch/dam/de/sd-web/QuwyTqPLhnpP/h0041folt-hta-report.pdf) - [S13-M1 · Full bibliographic/abstract web document](https://pubmed.ncbi.nlm.nih.gov/23543547/) - S13-M2 · Full text of the review paper: Material URL unverified; external material unread.