{ "schema_version": "chamgap-public-criteria-1.0", "title": "Folic acid, single added active ingredient by mouth × Hemoglobin increase in confirmed folate-deficient megaloblastic anemia", "criteria_version": "NGM-v3108-ISOLATED-FOLATE-ANEMIA-HB-1.1", "criteria_date": "2026-10-05", "condition_origin": "Chamgap application criteria", "method_sources": [ { "id": "M03", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03", "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13", "official_principle": "Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.", "review_level": "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." }, { "id": "M04", "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04", "section": "§4.5, §4.6.1–4.6.3, MECIR C42", "official_principle": "Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.", "review_level": "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." }, { "id": "M08", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08", "section": "§8.1–8.2.3, Table 8.2.a", "official_principle": "Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.", "review_level": "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." }, { "id": "M15", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15", "section": "§15.2.4, §15.3.1–15.3.3", "official_principle": "Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.", "review_level": "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." }, { "id": "M19", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19", "section": "§19.1.2, §19.2.1–19.2.4", "official_principle": "Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.", "review_level": "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." } ], "status_dictionary": { "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." }, "requirements": [ { "item_id": "N01", "question_type": "Boundary of the distinct claim", "question": "Which population with deficiency, oral folic acid comparison and Hb outcome does this table address?", "needed": "The current original claim and specifications for laboratory confirmation, B12 exclusion, ingredient, route, background care and control, Hb and time point", "role": "Required", "role_reason": "Required to distinguish the historical combined claims about anemia, pregnancy and cardiovascular outcomes from the current single Hb question.", "application_exception": "Verifying the identity of the question does not verify the existence of an eligible comparison or the magnitude of the treatment effect.", "criterion": "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.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Future comparisons should first specify this population and the Hb effect of interest, and report other etiologies and endpoints as separate questions." }, { "item_id": "N02", "question_type": "Laboratory confirmation and B12 exclusion", "question": "How were isolated folate deficiency and megaloblastic anemia confirmed, and how was B12 deficiency excluded?", "needed": "The original diagnostic framework, serum/RBC folate, Hb/MCV, marrow, B12 and functional markers, and exclusion criteria", "role": "Required", "role_reason": "Required to avoid defining a confirmed isolated-deficiency population solely from low folate or an anemia heading.", "application_exception": "Unverified test details do not establish that no diagnosis was made. Inaccessible NICE cutoffs are not inserted as new criteria.", "criterion": "Cross-check confirmation of diagnosis and exclusion of mixed deficiency in the selected population against the actual locations of the test records.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Record the diagnostic and B12-exclusion procedures, and separate results for the confirmed isolated-deficiency population from those for other deficiency strata." }, { "item_id": "N03", "question_type": "Other etiologies and special populations", "question": "Were groups with other etiologies, including pregnancy, mixed deficiencies, drugs, alcohol and malabsorption, distinguished?", "needed": "Information on diagnosis by etiology, coexisting deficiencies, pregnancy/lactation, age, liver and kidney status, drugs and malabsorption", "role": "Required", "role_reason": "Required to avoid combining material with different etiologies and treatment conditions solely because it shares the name anemia.", "application_exception": "Recovery in groups with other etiologies is preserved, and the reasons for exclusion are not used to claim no effect in those groups.", "criterion": "Specify the differences between the question about isolated deficiency in nonpregnant adults and the actual populations in related material.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Future studies should distinguish mixed deficiencies and special etiologies in advance and present direct comparisons separately for each population stratum." }, { "item_id": "N04", "question_type": "Chemical form and product identity", "question": "Were folic acid and the actual dosage form, manufacturer and product in an eligible comparison verified?", "needed": "Original records of chemical form, salt, sole active ingredient, dosage form, manufacturer, brand, batch and purity", "role": "Required", "role_reason": "Required to avoid treating folinic acid, 5-MTHF and combination products as the same intervention.", "application_exception": "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.", "criterion": "Separate the folic acid specified in the question from the extent to which the product in an actual comparison has been verified.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Record the identifiable single-ingredient folic acid product and each group's product, batch, purity and other active ingredients." }, { "item_id": "N05", "question_type": "Route, dose and duration", "question": "Were the dose, dosing frequency, treatment duration and exposure of an eligible oral regimen verified?", "needed": "Original data on route, daily dose, dosing frequency, total exposure, treatment duration and concurrent supplementation for each eligible group", "role": "Required", "role_reason": "Required to avoid turning other routes, product labeling or doses from related trials into the regimen for the main question.", "application_exception": "The route in the question is oral, but the actual dose and duration of an eligible regimen remain unverified. No individual dose is specified.", "criterion": "Link only exposure from the actual comparison, and attribute labeled doses and doses used in groups with other etiologies separately.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Record actual use, adherence and concurrent supplementation for the sole oral addition, and directly compare justified dose/duration questions." }, { "item_id": "N06", "question_type": "Same background care and actual control", "question": "Were background treatment apart from folic acid and a control without added folic acid actually compared?", "needed": "Original records of background treatment, concurrent supplementation, diet, transfusion, rescue treatment and the control without added folic acid for each group", "role": "Required", "role_reason": "Required to avoid attributing before-and-after recovery or asymmetric treatment changes to a between-group effect of folic acid alone.", "application_exception": "Shared treatment is not itself a reason for exclusion. Withholding treatment is not assumed to be acceptable, and ethically appropriate comparisons are distinguished.", "criterion": "Link the contrast for added folic acid under the same background care to the actual differences in background care.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Define the ethically permissible comparison and effect of interest, and report background treatment, rescue treatment and changes by group." }, { "item_id": "N07", "question_type": "Hb measurements and other endpoints", "question": "Is the primary outcome the between-group change in Hb, distinguished from MCV, reticulocytes, folate and other measures?", "needed": "Hb definition, change/final values, units, direction of comparison, predefined follow-up time and a list of other endpoints", "role": "Required", "role_reason": "Required to avoid substituting other biochemical recovery for Hb comparison values.", "application_exception": "Trials of survival or transfusion events are not unconditionally required for a question about Hb itself. Such extensions require separate evidence.", "criterion": "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.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Define Hb measurement and analysis in advance, and report other markers, symptoms, transfusion and correction rates as separate outcomes." }, { "item_id": "N08", "question_type": "Predefined time point and follow-up coordinates", "question": "Can the fixed Hb follow-up time in an eligible comparison be distinguished from treatment and observation durations?", "needed": "Original registration/protocol records of the primary Hb time point, measurement schedule, treatment, discontinuation and follow-up duration", "role": "Required", "role_reason": "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_exception": "Golding's days 586, 588 and 772 are study-day coordinates, not a prescribed general recovery timetable.", "criterion": "Distinguish the predefined follow-up time of an eligible comparison from time coordinates in related material.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Specify treatment exposure and the Hb follow-up schedule, and measure the effects of continuation and discontinuation as separate questions defined in advance." }, { "item_id": "N09", "question_type": "Hb testing and measurement conditions", "question": "Were Hb measurement and differences in transfusion, bleeding and testing that affect anemia verified?", "needed": "Records of the Hb assay, units, specimen/collection schedule, assessor blinding, transfusion, bleeding and changes by group in an eligible comparison", "role": "Required", "role_reason": "Required to distinguish measurement and clinical conditions contributing to Hb change from the contribution of folic acid.", "application_exception": "Failure to verify a measurement method in the current material is not expanded into a claim that it was unreported throughout the original paper.", "criterion": "Link Hb measurement conditions and the effects of other treatment or physiological changes to the actual comparison.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Standardize testing and specimen schedules, transfusion/bleeding and concurrent treatment, or report the actual differences and how they were handled analytically." }, { "item_id": "N10", "question_type": "Eligible comparative design", "question": "Were the actual comparative design, allocation and baseline balance in the isolated-deficiency population verified?", "needed": "Original records of selection, design, allocation/concealment, baseline status, background care and control, and denominators in an eligible comparison", "role": "Required", "role_reason": "Required to distinguish the existence of human research from a direct comparative design for the selected question.", "application_exception": "Prospective observations are also preserved. Randomized placebo comparisons are not newly designated as the sole permissible evidence for replacement treatment.", "criterion": "Separate the currently known designs from the unverified status of a direct comparison in the isolated-deficiency population.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Specify an ethically permissible prospective comparison and the effect of interest, and record selection/allocation and baseline confounding." }, { "item_id": "N11", "question_type": "Golding: design and denominator for 1 participant", "question": "Were the participant count and the number of analytical replicates in Golding's self-experiment distinguished?", "needed": "Original records of the self-experiment's design, participant/randomized/control counts and repeated tests", "role": "Required", "role_reason": "Required to avoid counting analytical replicates or specimens as new participants or independent comparisons.", "application_exception": "Recovery in 1 person is retained as information but is not converted into a between-group effect or population incidence.", "criterion": "Link the depletion-and-recovery trajectory of one person to the implications of having no concurrent control.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "In prospective data, report participants, specimens and analytical replicates separately, and specify the limitations of the comparison." }, { "item_id": "N12", "question_type": "Golding: recovery and graphs", "question": "To what extent were Golding's Hb recovery timing and graph values read?", "needed": "The depletion-and-repletion timeline, reported Hb trajectory and extent of reading of the original graph", "role": "Required", "role_reason": "Required to preserve favorable recovery without converting an uncontrolled trajectory into an effect estimate.", "application_exception": "The graphs are not digitized, and the Hb value at the nadir is not reconstructed.", "criterion": "Retain the study-day coordinates and recovery narrative without turning them into a quantitative between-group comparison.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Observational studies should report Hb trajectories, times of changes and conditions that changed together, and distinguish causal effects from descriptive data." }, { "item_id": "N13", "question_type": "Golding: concurrent diet and B12", "question": "Were Golding's resumption of normal diet and concurrent B12 use distinguished from the contribution of folic acid?", "needed": "Original records of diet, folate, methylcobalamin, B12 tests and times of changes", "role": "Required", "role_reason": "Required to avoid attributing simultaneous dietary changes and cointerventions to the effect of folic acid alone.", "application_exception": "B12 monitoring and methylcobalamin administration are not treated as equivalent to diagnostic exclusion.", "criterion": "Link concurrent B12 at 1000 µg/day and resumption of diet to the context of the self-experiment.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_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." }, { "item_id": "N14", "question_type": "Olaparib: directness of the population", "question": "Is Shammo's cancer/olaparib population the same as a population with confirmed isolated folate-deficiency anemia?", "needed": "Original data on cancer/drugs, anemia/folate diagnosis, and the stratum with megaloblastic anemia and B12 deficiency excluded", "role": "Required", "role_reason": "Required to avoid transferring a comparison in cancer- or drug-induced anemia to isolated nutritional deficiency.", "application_exception": "The randomized component in the related material is not disregarded; the population mismatch and the unverified effect are retained separately.", "criterion": "Explain the differences between the olaparib-related population and the confirmed isolated-deficiency population, and the unverified status of the separately defined stratum.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Separate population strata with drug-induced causes from those with isolated deficiency, and report Hb comparisons by stratum." }, { "item_id": "N15", "question_type": "Olaparib: enrollment, allocation and completion", "question": "Were the 9 enrolled participants, the 2+2 allocated participants and the 12-month completion denominator distinguished?", "needed": "Original flow records for consent, enrollment, randomization, nonrandomization, completion and Hb analysis by group", "role": "Required", "role_reason": "Required to avoid using the entire cohort as the denominator for randomized Hb analyses.", "application_exception": "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.", "criterion": "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.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Report the flow of the entire cohort separately from that of the allocated subgroup, and provide analysis denominators at each Hb time point." }, { "item_id": "N16", "question_type": "Olaparib: dose and rescue criteria", "question": "To which trial do Shammo's 1 mg/day dose and folate/Hb allocation and rescue criteria belong?", "needed": "The original trial dose, folate/Hb allocation criteria, rescue policy and actual use by group", "role": "Required", "role_reason": "Required to avoid extending an oncology trial's protocol into general diagnostic confirmation criteria or a treatment regimen.", "application_exception": "Rescue at Hb <10 g/dL is this trial's original protocol, not a threshold for withholding treatment from patients generally.", "criterion": "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.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Record the ethical rescue policy, actual timing of use and denominators, and specify its impact in the analysis of the effect of interest." }, { "item_id": "N17", "question_type": "Olaparib: change in control", "question": "Were Shammo's change from the placebo plan and the actual control without supplementation distinguished?", "needed": "The original plan, reasons for changes, open-label/blinding status, actual control without supplementation and analysis documents", "role": "Required", "role_reason": "Required to avoid presenting the initially planned placebo as an actual blinded trial.", "application_exception": "The cost-related change is recorded, but the lack of an obtained protocol is not converted into a confirmed finding of selective reporting.", "criterion": "Link the abandonment of placebo and the comparison without supplementation to the actual design, and distinguish the amendment history.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Transparently report the plan, reasons for changes, actual control, blinding and Hb analysis of interest." }, { "item_id": "N18", "question_type": "Olaparib: conflicting trial-phase wording", "question": "Were the phase IV and phase II/single-arm labels recorded in Shammo's original text preserved without arbitrarily harmonizing them?", "needed": "The relevant original pages, design wording, corrections or author explanations", "role": "Required", "role_reason": "Required to avoid inferring one actual phase from inconsistent design labels within the same report.", "application_exception": "The wording conflict is reported in the currently retained citation; the original full text was not independently rechecked in this review.", "criterion": "Preserve the discrepancy between p.1/3 phase IV and the p.2 phase II/single-arm template, together with their locations.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Align design labels with the actual allocation component, and record an original explanation or correction as a separate event when available." }, { "item_id": "N19", "question_type": "Olaparib: Hb and background medication", "question": "Were Shammo's interpretation of secondary Hb results and olaparib dose reduction kept from being converted into a between-group effect?", "needed": "Secondary Hb results, medication changes by group, formal Hb estimates/variance/time points and the original protocol", "role": "Required", "role_reason": "Required to avoid turning folate recovery, author narratives and asymmetric medication changes into a formal Hb effect.", "application_exception": "The authors' interpretation of Hb is preserved, but nonsignificance or unverified quantitative information is not used as equivalence or an effect of 0.", "criterion": "Attribute the primary frequency/timing of folate deficiency, secondary Hb and olaparib dose reduction in controls to their respective roles.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_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." }, { "item_id": "N20", "question_type": "Alcohol and malabsorption material", "question": "How were Clarke's case and Sheehy's tropical-sprue material preserved?", "needed": "Case etiology, cointerventions/transfusion, administration/control, B12 exclusion, Hb values and the actual extent of access", "role": "Required", "role_reason": "Required to preserve related hematologic recovery without counting it as replication in isolated deficiency.", "application_exception": "Limited full-text access is not expanded into a claim of nonreporting in the original text or absence of research in this review.", "criterion": "Specify the differences between Clarke's 1-person case with mixed etiologies and Sheehy's malabsorption/dose-titration setting.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Report etiology, concurrent treatment, tests and denominators separately, and evaluate them through a comparison appropriate to that population's question." }, { "item_id": "N21", "question_type": "Folate markers in people without anemia", "question": "Does Obeid's folate-marker study in nonpregnant women provide an Hb treatment result in confirmed anemia?", "needed": "Actual anemia diagnosis, baseline status, Hb outcomes, folate markers and the location of the selection information", "role": "Required", "role_reason": "Required to avoid inferring a treatment effect solely from the shared characteristic of being nonpregnant or from folate recovery.", "application_exception": "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.", "criterion": "Record the difference between biomarker supplementation material in people without anemia and the treatment question in confirmed megaloblastic anemia.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Separate baseline anemia and deficiency from outcomes, and provide a direct Hb comparison when the question concerns Hb treatment." }, { "item_id": "N22", "question_type": "Combined B vitamins in MS", "question": "Can Nozari's combined B12+folic acid intervention in MS be separated into an effect of folic acid alone?", "needed": "The MS population, B12/folic acid interventions by group, Hb/anemia/quality-of-life outcomes and a contrast with a sole added ingredient", "role": "Required", "role_reason": "Required to avoid attributing combination results to folic acid alone when both the population and the added active ingredients differ.", "application_exception": "The favorable context of the combination data is preserved, and effects of individual ingredients are not arbitrarily disentangled.", "criterion": "Link MS and the addition of two active ingredients to their differences from the main population/intervention.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "If the question concerns each ingredient's contribution, design a direct contrast with matched background care and separate outcomes by disease." }, { "item_id": "N23", "question_type": "Pregnancy review and reused citation", "question": "Were the pregnancy review and trials from historical record 121 kept from being counted as independent replications of replacement treatment in adults?", "needed": "The actual populations and prevention/treatment questions of the review/included trials, and links to original data", "role": "Required", "role_reason": "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_exception": "The original file for historical record 121 was not read in this review; only the reused citation record in the current 3108 was read.", "criterion": "Distinguish a pregnancy-prevention review from Hb treatment in nonpregnant people with isolated deficiency, and do not infer the number of direct replications.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Link included trials to unique study families and their actual populations, interventions and outcomes, then separately review only material relevant to the question." }, { "item_id": "N24", "question_type": "Between-group effect, variance and interval", "question": "Were the direct Hb difference in change, adjusted difference in final values, and SD/SE, CI and P verified?", "needed": "Original tables of Hb values/changes, units, n and SD/SE for each eligible group, the estimation model, CI and P", "role": "Required", "role_reason": "Required to avoid filling absent direct values with 0 or reconstructing them from graphs or other markers.", "application_exception": "Keep the variance type and CI unverified when they are unverified, and do not determine precision from sample size alone.", "criterion": "Separate between-group change from the adjusted difference in final values, and specify that variance, intervals and tests remain unverified.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_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." }, { "item_id": "N25", "question_type": "Analysis population and missing data", "question": "Were ITT/PP, completion/analysis denominators, missing data and Hb analysis in the main comparison verified?", "needed": "Flow, Hb measurement/analysis n, ITT/PP, reasons for and handling of missing data, and sensitivity analyses for each eligible group", "role": "Required", "role_reason": "Required to avoid turning enrollment, allocation or before-and-after measurement counts into actual Hb analysis denominators.", "application_exception": "Unverified analysis details are not converted into randomization failure, confirmed selective reporting or 0 missing observations.", "criterion": "Separate allocation, completion and analysis, and link the selected effect of interest to the unverified status of the actual analysis.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_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." }, { "item_id": "N26", "question_type": "Important difference and extension to clinical outcomes", "question": "Were the clinical importance of Hb and questions about symptoms, transfusion and survival distinguished?", "needed": "A justified criterion for an important Hb difference in the relevant population, and direct outcomes for symptoms, transfusion and quality of life/survival", "role": "Supplementary; required for claims about importance or extension to event outcomes", "role_reason": "Required to avoid extending the clinical scope of treatment benefit solely from a laboratory change.", "application_exception": "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.", "criterion": "Distinguish the degree to which an Hb importance criterion is verified from the degree to which separate event evidence is verified.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Justify an important Hb difference for the population and context, and measure patient-centered events as separate outcomes." }, { "item_id": "N27", "question_type": "Study families, funding and disclosures", "question": "To what extent were each report's family and funding/product/conflict-of-interest information verified?", "needed": "Unique-study/reused-citation relationships and original wording on research funding, product provision and author disclosures", "role": "Supplementary; required for a claim of independence", "role_reason": "Required to avoid inferring independent replication or verified funding solely from 13 reports and location references.", "application_exception": "Unverified conflicts of interest are not treated as independent support, and product documents are identified as manufacturer material.", "criterion": "Link evidence study_id, shared registration and material roles, and leave funding unverified where the original text is unavailable.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Disclose family relationships, overlapping reports, funding and product roles, and verify independent direct comparisons through actual links." }, { "item_id": "N28", "question_type": "Registration, protocol and hierarchy", "question": "Were the registry shell and the original protocol/SAP, amendment history and current status distinguished?", "needed": "The original NCT04024254 registration/history, protocol, SAP, Hb hierarchy/time points and reasons for amendments", "role": "Required", "role_reason": "Required to avoid turning the existence of a registration number into proof of preregistration, endpoint agreement or current completion.", "application_exception": "Limited access to the original protocol does not establish nonregistration or selective reporting. It is also not a failed access attempt in this review.", "criterion": "Separate the retained identifier linkage from unverified registration timing, history and current status.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Link the Hb outcome, time point and analysis of interest, and actual amendments, to public records and cross-check them against actual reporting." }, { "item_id": "N29", "question_type": "B12 guideline version", "question": "Were BSH's replacement notice and the unverified NICE details distinguished?", "needed": "BSH version/update notices, the identity of NICE NG239 and the actual original diagnostic/treatment recommendations", "role": "Supplementary; required for diagnostic and safety applications", "role_reason": "Required to avoid presenting an old guideline as unchanged current guidance or filling in diagnostic criteria that have not been read.", "application_exception": "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.", "criterion": "Separate the 2024 replacement notice for the 2014 document from the unverified scope of the original recommendations.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "When updating diagnostic/safety criteria, cross-check the actual original recommendations, version, applicable population and reasons for changes." }, { "item_id": "N30", "question_type": "HTA of folate testing", "question": "Was the Swiss HTA's evidence on testing utility kept from being transferred into a claim of no effect of folic acid treatment?", "needed": "The HTA's question about the clinical utility of testing, original sections/pages and distinction from the treatment context", "role": "Required", "role_reason": "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_exception": "Historical reading of some HTA narrative does not verify values in the original appendices or diagnostic cutoffs.", "criterion": "Separate the question of folate testing from the question of Hb treatment in isolated deficiency.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Evaluate patient outcomes and treatment comparisons for a testing strategy separately from direct replacement-treatment effects as distinct research questions." }, { "item_id": "N31", "question_type": "Official treatment context and labeled regimen", "question": "Were recognized replacement treatment and the dose on the S11 label distinguished from a direct comparative effect?", "needed": "S11 product identity, indication, labeled dose/duration and version, and the identity of an eligible trial", "role": "Required", "role_reason": "Required to avoid turning an authorized indication or 5 mg/4 months into a trial effect estimate or individual dosing instructions.", "application_exception": "An unverified direct effect is not interpreted as recognized treatment being unnecessary or as advice to delay treatment.", "criterion": "Retain recognized replacement treatment and product labeling, while separating them from verified between-group results and regimens.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Use labeling as treatment context, and report the actual comparison, exposure and Hb outcomes for the question of interest separately." }, { "item_id": "N32", "question_type": "RE and treatment-ethics boundaries", "question": "Were the original nonapplication of RE, allowance for prospective observation and prohibition on withholding treatment retained unchanged?", "needed": "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", "role": "Required", "role_reason": "Required to avoid turning the exception logic of the current original verdict into a new score, a mandatory placebo requirement or treatment delay.", "application_exception": "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.", "criterion": "Preserve the allowance for prospective observation and the gates that were not established, and record the original RE_eligible=false unchanged.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_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." }, { "item_id": "N33", "question_type": "B12 masking and neurological risk", "question": "Was improvement in Hb distinguished from resolution of neurological problems due to B12 deficiency?", "needed": "S11 contraindications and precautions for B12 deficiency/undiagnosed anemia, and actual neurological-harm definitions and exposure/denominator data", "role": "Supplementary; required for safety boundaries", "role_reason": "Required to avoid implying that hematologic improvement means resolution of B12 deficiency or neurological safety.", "application_exception": "The official warning is product context and does not determine incidence or individual risk in the isolated-deficiency population.", "criterion": "Record warnings about masking B12 findings and delayed recognition separately from Hb recovery and unverified frequency.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Record B12 exclusion and neurological observations, and separately collect actual harm definitions, timing, exposure and denominators." }, { "item_id": "N34", "question_type": "Adverse reactions, drugs and denominators", "question": "Were gastrointestinal and allergic reactions and interactions distinguished from actual event denominators in the eligible population?", "needed": "Original data on AE/SAE, discontinuation, exposure/duration, collection methods, people with events/event counts and concomitant drugs for each eligible group", "role": "Supplementary; required for frequency/safety claims", "role_reason": "Required to avoid turning a product's reaction list into comparative event rates or absence of risk in the main population.", "application_exception": "The statuses Not read and Unverified are not converted into 0 people with adverse reactions/SAE/discontinuation.", "criterion": "Distinguish S11's gastrointestinal/allergic and antiepileptic/methotrexate context from the gap in direct event rates.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Report harm definitions, systematic collection, people/event counts, exposure time and denominators by group, and analyze drug interactions in their relevant context." }, { "item_id": "N35", "question_type": "Long-term use and special populations", "question": "Can safety/efficacy be extended to high doses, long-term use, liver or kidney disease, cancer, malabsorption, pregnancy/lactation and children?", "needed": "Actual exposure/effect by population, dose and duration, rare/long-term harms, and drug/underlying-disease data", "role": "Supplementary; required for extension claims", "role_reason": "Required to avoid extending related product context or brief recovery to safety/efficacy in all populations.", "application_exception": "Studies in every special population are not imposed as mandatory for the original Hb question, and individual dosing instructions are not provided.", "criterion": "Record the question about nonpregnant adults with isolated deficiency separately from the unverified scope for each special population.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "For each extension question, separately collect appropriate design, exposure, long-term follow-up and outcomes in vulnerable populations." }, { "item_id": "N36", "question_type": "Current and historical reading", "question": "Was historical access for the 13 bibliographic records distinguished from reading local summaries in this review?", "needed": "Material type, URL, historical access_level/flag, dates and original locations for each report, and exact current stored-summary anchors", "role": "Required", "role_reason": "Required to avoid upgrading original full-text access flags and links into full-text reading in this review.", "application_exception": "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.", "criterion": "Separate actual reading, acquisition and access status by material type into current and historical records, and leave records without access dates empty.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "During any authorized subsequent material check, record original locations, material type, dates, acquisition/reading and access failures separately." }, { "item_id": "N37", "question_type": "Original-verdict and publication boundaries", "question": "Were the original ?/empty values, axes, safety and publication records distinguished from the new criteria statuses?", "needed": "Original grade/score/axes, calculation, evidence_status, publication/server metadata and the scope of the new table", "role": "Required", "role_reason": "Required to avoid carrying over the original score or internal deployment metadata as new efficacy, safety or completed public website publication.", "application_exception": "The original first_published_at is the content baseline date; server_deployed and server_write=false are retained records.", "criterion": "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.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_research": "Separate material/criteria updates from the original clinical verdict and events of public release, preserving the original text before and after changes." }, { "item_id": "N38", "question_type": "Search limitations and links to updates", "question": "What would actually update the gaps within the retained search scope of 2026-09-15?", "needed": "New direct Hb results, actual original texts/protocols, corrections/retractions, and evidence of numerical, classification, diagnostic and safety changes", "role": "Required", "role_reason": "Required to avoid turning a limited current value into an up-to-date exhaustive search or a claim of permanent absence.", "application_exception": "This is not a new search, correction/retraction lookup, calculation or reassessment. Revision of criteria and addition of evidence are separate events.", "criterion": "Record the original cutoff date, incompleteness, unchanged ID/URL, reasons for changes and re-review of linked rows.", "basis": "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", "condition_origin": "Case-specific necessary criteria were designed internally and reviewed by the model with the current material already known. This was not blinded review, clinical preregistration or official methodological certification.", "proposed_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." } ] }