{ "schema_version": "chamgap-public-criteria-1.0", "title": "Oral vitamin B12 as the sole added active ingredient × Improvement in global cognition in adults with clinically defined MCI", "criteria_version": "NGM-v3112-ORAL-B12-MCI-GLOBAL-1.0", "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 actual retained copy/SHA and the methodological principles used at the time for 1585 were reused as historical material. This exercise did not newly read full methodological texts, perform an official method or provide clinical certification." }, { "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 actual retained copy/SHA and the methodological principles used at the time for 1585 were reused as historical material. This exercise did not newly read full methodological texts, perform an official method or provide clinical certification." }, { "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 actual retained copy/SHA and the methodological principles used at the time for 1585 were reused as historical material. This exercise did not newly read full methodological texts, perform an official method or provide clinical certification." }, { "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 actual retained copy/SHA and the methodological principles used at the time for 1585 were reused as historical material. This exercise did not newly read full methodological texts, perform an official method or provide clinical certification." }, { "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 actual retained copy/SHA and the methodological principles used at the time for 1585 were reused as historical material. This exercise did not newly read full methodological texts, perform an official method or provide clinical certification." } ], "status_dictionary": { "Met": "The relevant criterion within the question/retained scope was verified. This does not establish efficacy.", "Partly verified": "Some records are verified, while gaps in the relevant direct criteria/material remain.", "Unverified": "The required direct values/criteria were not 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": "A printing/counting conflict within the same material is explicitly recorded in the original retained record. It was not independently reverified against the original source in this exercise.", "Not applicable": "There is a reason not to impose the criterion on the narrow question.", "Not read": "The relevant external material was not actually read in this exercise." }, "requirements": [ { "item_id": "N01", "question_type": "Claim and boundaries of the distinct question", "question": "Which MCI population, B12 comparison and global cognition outcome does this table address?", "needed": "Original claim and fixed question; specifications of population, ingredient, route, outcome, comparator and timepoint", "role": "Required", "role_reason": "Required to avoid combining the page's cognition, dementia and deficiency questions into a single efficacy claim.", "application_exception": "Verification of the claim boundaries does not establish an eligible trial or an improvement effect.", "criterion": "Link the oral comparison in MCI with B12 as the sole added active ingredient to the global cognition score, and exclude other questions.", "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; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Subsequent research should first specify clinical MCI and the between-group effect of interest on a global cognition scale, with conversion to dementia, imaging and biochemical outcomes reported separately." }, { "item_id": "N02", "question_type": "Clinical MCI diagnosis", "question": "Does the MCI label in Ma2019 satisfy the actual clinical diagnostic criteria?", "needed": "Original material on the diagnostic system, diagnostician, objective criteria, ADL, dementia exclusion, subtypes and age/sex", "role": "Required", "role_reason": "Required to avoid treating the diagnostic label alone as verification of confirmed MCI, preserved daily functioning or exclusion of dementia.", "application_exception": "Do not turn unverified detailed criteria into a definite conclusion that the participants did not have clinical MCI.", "criterion": "Assess population directness by distinguishing the reported MCI label from unverified diagnostic details.", "basis": "M03 §3.2.1; detailed population criteria are internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Document diagnostic criteria and procedures for assessing daily functioning and excluding dementia, prespecify MCI subtypes and present results by population." }, { "item_id": "N03", "question_type": "Baseline B12 status", "question": "Can correction of deficiency be distinguished from supplementation in replete or unverified status?", "needed": "Baseline B12/holotranscobalamin/MMA, homocysteine, folate, Hb/MCV, deficiency thresholds and results by stratum", "role": "Required", "role_reason": "Required to avoid extending correction of deficiency-related cognitive impairment to MCI efficacy regardless of status.", "application_exception": "Do not fill in unreported baseline tests with assumptions of replete status or normal hematologic status.", "criterion": "Link only the verified scope of baseline status, thresholds and direct results in each stratum.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Prespecify baseline B12 status categories, and separately analyze interactions/stratified comparisons for correction of deficiency and add-on treatment in replete status." }, { "item_id": "N04", "question_type": "Chemical form and product identity", "question": "Were the actual chemical form, formulation and product in the B12 monotherapy arm verified?", "needed": "Original records of chemical form, salt, manufacturer, dosage/release formulation, product, batch and purity", "role": "Required", "role_reason": "Required to avoid combining different cobalamin chemical forms and products as the same intervention.", "application_exception": "Distinguish the question's definition of a single active ingredient from verification of the actual trial product.", "criterion": "Link the actual product attributes of the monotherapy arm to original material, retaining missing values.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Use an identifiable single-ingredient B12 formulation and report product, batch, purity and exposure to the chemical form by arm." }, { "item_id": "N05", "question_type": "Plant part not applicable", "question": "Should this question require distinctions between plant parts?", "needed": "Distinction between a chemical nutrient intervention and a plant-derived intervention", "role": "Supplementary", "role_reason": "Considered to avoid mechanically imposing a plant-part criterion on a chemical nutrient question.", "application_exception": "Nonapplicability of plant part does not waive verification of the manufacturer, product or purity.", "criterion": "Link the retained reason that plant_part is not applicable to the chemical ingredient question.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Obtain actual B12 product and chemical-form material to assess identity criteria without adding plant-part research." }, { "item_id": "N06", "question_type": "Oral route", "question": "Was oral administration in the B12 monotherapy arm verified from original material?", "needed": "Route, formulation and schedule by arm, and the original methods for the monotherapy arm", "role": "Required", "role_reason": "Required to avoid treating the word oral for the combination arm as verification of the monotherapy arm's route.", "application_exception": "Distinguish the review's oral-route lead from verification of the original monotherapy arm.", "criterion": "Distinguish the page's oral-route question from the actual oral combination arm and the unverified monotherapy arm.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Specify oral administration and its schedule in the monotherapy arm, and report injection, sublingual and mixed routes as separate comparisons." }, { "item_id": "N07", "question_type": "Actual dose and secondary (2nd) leads", "question": "Can 25 µg/day be used as the established monotherapy-arm dose?", "needed": "Original amount per administration (1 time), daily amount and frequency in the monotherapy arm, and the original source cited by the review", "role": "Required", "role_reason": "Required to avoid turning the review's dose lead into a verified value for the original monotherapy arm or a personal dose.", "application_exception": "Retain the lead without promoting it to an established daily amount, amount per administration (1 time) or frequency.", "criterion": "Distinguish the reports of B12 25 µg and folic acid 800 µg as secondary (2nd) information, and preserve the unverified original monotherapy-arm dose.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Report chemical form, amount per administration (1 time), frequency and daily amount by arm, and formulate a separate question when conducting a direct dose comparison." }, { "item_id": "N08", "question_type": "Same folic acid background", "question": "Does the combination-arm versus folic-acid-arm comparison differ only in B12?", "needed": "Folic acid dose, same background treatment, added ingredients and actual exposure in both C02 arms", "role": "Required", "role_reason": "Required to avoid attributing multiple active ingredients or different backgrounds to an added B12 effect.", "application_exception": "Do not automatically exclude the comparison: if folic acid dose and background are the same in both arms, it may be a candidate for an added B12 effect.", "criterion": "Interpret the contrast as B12 being the sole added ingredient only when the matched background is verified.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Randomize only added B12 on the same folic acid and usual-care background, and prespecify analysis of the same global cognition effect." }, { "item_id": "N09", "question_type": "Actual control arm", "question": "Was an untreated control distinguished from matched placebo and the same care?", "needed": "Actual treatment, placebo composition, background and rescue treatment in the control arm", "role": "Required", "role_reason": "Required to avoid presenting an untreated arm as a blinded matched placebo arm.", "application_exception": "Do not erase the existence of the actual untreated arm because placebo composition is unverified.", "criterion": "Distinguish the reported untreated control from the page's eligible comparator criteria.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Document the actual treatment and the same background in the comparator of interest, and examine differences in contact and assessment in the analysis." }, { "item_id": "N10", "question_type": "Adherence and concurrent exposure", "question": "Were actual total B12 exposure and conditions affecting absorption or concomitant use distinguished?", "needed": "Records by arm of adherence/measurement method, diet/fortification/additional supplements, malabsorption and metformin/PPI", "role": "Required", "role_reason": "Required to avoid confusing diet, other supplements and conditions affecting absorption with the randomized dose.", "application_exception": "Do not fill in unreported information with normal absorption, high adherence or absence of concomitant use.", "criterion": "Distinguish the nominal intervention from actual exposure and background differences according to their verification level.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Track exposure, adherence, absorption and concomitant medications, and prespecify separate analyses of the assignment effect and adherence-related effects." }, { "item_id": "N11", "question_type": "Reported duration and main timepoint", "question": "Was the reported 6-month timepoint verified as the prespecified main timepoint?", "needed": "Administration period, assessment timepoints, registered main timepoint and records of endpoint changes", "role": "Required", "role_reason": "Required to avoid confusing the reported duration with the prespecified main analysis timepoint.", "application_exception": "Preserve the page's 6-month review timepoint without labeling it as the registered main timepoint.", "criterion": "Distinguish the 6-month report from the verification level of preregistration and analysis timepoints.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Prespecify the main assessment timepoint for global cognition, and report later timepoints and follow-up after discontinuation as separate analyses." }, { "item_id": "N12", "question_type": "Global scale and measurement", "question": "Were the actual testing conditions for WAIS-RC FSIQ verified?", "needed": "Scale version/manual, score range, language, education adjustment, administration/practice effects and direction", "role": "Required", "role_reason": "Required to avoid substituting another cognitive scale or a domain result for the same global score outcome.", "application_exception": "Preserve the reported scale and direction without inferring its version or score range.", "criterion": "Distinguish the reported WAIS-RC FSIQ from unverified testing conditions.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Administer the same validated global scale using standardized procedures, with prespecified handling of education, language and repeated-testing effects." }, { "item_id": "N13", "question_type": "Registration and prespecified hierarchy", "question": "Was the prespecified primary endpoint on the global scale checked against the ChiCTR record?", "needed": "Original registration date, original/changed endpoints, protocol, SAP and reasons for changes", "role": "Required", "role_reason": "Required to avoid treating the existence of a registration number as successful comparison against the protocol/SAP.", "application_exception": "Distinguish historical access failure from access not attempted in this exercise, without establishing nonregistration or selective reporting.", "criterion": "Label primary status only according to the hierarchy actually obtained, and retain the unavailable information as such.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Link the registration, protocol and SAP in advance and make the original/changed endpoints available for comparison with reported results." }, { "item_id": "N14", "question_type": "Design and allocation", "question": "Were the actual sequence and allocation concealment for the 4-arm randomization verified?", "needed": "Allocation sequence, concealment, baseline balance and recruitment/selection procedures by arm", "role": "Required", "role_reason": "Required to avoid claiming that the randomized-trial label alone resolves allocation bias concerns.", "application_exception": "Retain the report of randomization and do not turn unverified information into a high-risk judgment.", "criterion": "Link the report of 4-arm randomization to the verification level of the actual allocation methods.", "basis": "M08 §8.1–8.2.3; internal application; 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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Disclose the allocation sequence, concealment and baseline characteristics by arm, and prespecify analysis of the assignment effect." }, { "item_id": "N15", "question_type": "Blinding and assessors", "question": "Who was blinded in the single-blind design?", "needed": "Participant/assessor/analyst blinding, procedures and contact by arm", "role": "Required", "role_reason": "Required to examine cognitive testing and differences in expectations/contact between arms.", "application_exception": "Do not turn unverified information about who was blinded into a definite finding of blinding failure.", "criterion": "Distinguish the single-blind label from unverified information about each role and assessment conditions.", "basis": "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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Specify blinding of cognitive assessors and analysts and contact by arm, and maintain matching assessment procedures." }, { "item_id": "N16", "question_type": "Allocation and historical arithmetic denominators", "question": "Were 240 participants, 4 arms and the inferred 60 participants distinguished from analysis denominators?", "needed": "Flow diagram of actual allocation, completion and analysis overall/by arm, distinguished from the historical calculation", "role": "Required", "role_reason": "Required to avoid turning the total randomized number and a historical arithmetic inference into original arm-specific analysis counts.", "application_exception": "Preserve the existing 60 participants only as a historical calculated value; do not recalculate it in this exercise.", "criterion": "Link the report of 240 participants and 4 arms to the verification level of the inferred 60 participants and the unverified original arm-specific counts.", "basis": "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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Publish a flow diagram of allocation, follow-up, completion and analysis denominators by arm, and provide the actual denominator for each outcome in tables." }, { "item_id": "N17", "question_type": "Analysis population and missing data", "question": "Were the monotherapy-arm analysis count, ITT/PP and handling of dropouts verified?", "needed": "Completion/analysis/dropouts by arm, ITT/PP, missing data/imputation and analysis population", "role": "Required", "role_reason": "Required to avoid treating the reported total alone as verification of complete follow-up or an ITT analysis.", "application_exception": "Do not fill in missing analysis denominators or dropout counts with 0 or 60.", "criterion": "Link the verification scope of the monotherapy-arm denominators and missing-data handling to the results.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Report actual denominators and reasons for missing data by arm, and prespecify the main analysis of the assignment effect, imputation and sensitivity analyses." }, { "item_id": "N18", "question_type": "Direct monotherapy-arm effect", "question": "Were the global cognition difference, CI and P for B12 alone versus control verified?", "needed": "Original monotherapy-arm between-group estimate for the main global cognition outcome, unit, timepoint, denominator, CI/P and original table", "role": "Required", "role_reason": "Required to avoid transferring combination-arm numbers or review wording to the original monotherapy-arm effect.", "application_exception": "The currently unverified direct values do not constitute a judgment of an effect of 0 or no effect.", "criterion": "Display an effect for the monotherapy contrast of interest only when its actual estimate is verified.", "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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Publish the prespecified between-group global cognition difference, CI and denominator for the B12 monotherapy contrast on the same background." }, { "item_id": "N19", "question_type": "Attribution of the positive combination-arm result", "question": "Which comparison do d = 0.169 and P = 0.024 refer to?", "needed": "Original abstract for the combination arm versus no treatment, effect definition/method of calculating d, timepoint and denominator", "role": "Required", "role_reason": "Required to avoid using the positive combination-arm result as the effect of B12 alone.", "application_exception": "Retain results that are not unfavorable as well, attributing them to the actual combination comparison.", "criterion": "Attribute the current positive numbers only to the actual combination contrast.", "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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Prespecify combination and monotherapy contrasts separately, and provide each contrast's between-group estimate, denominator, CI and effect definition separately." }, { "item_id": "N20", "question_type": "Conditional add-on effect", "question": "How is the favorable post hoc statement for combination versus folic acid preserved?", "needed": "Original C02 results, same background, estimate/CI/P and whether the contrast was prespecified", "role": "Required", "role_reason": "Required to consider the possibility of the same folic acid background without turning a conditional candidate into a confirmed comparison.", "application_exception": "Do not delete the favorable statement because it comes from a post hoc comparison, but do not promote it to a prespecified primary endpoint.", "criterion": "Record the conditional add-on candidate together with the currently unverified eligible numbers.", "basis": "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 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Prespecify the added B12 contrast on the same folic acid background, and disclose the main global cognition result, interval and handling of multiple comparisons." }, { "item_id": "N21", "question_type": "Model and printed post hoc method", "question": "Were the repeated-measures model and the printed Turkey distinguished from the actual analysis?", "needed": "Original analysis section, model/covariates for each contrast, post hoc method, multiple comparisons and main/sensitivity distinction", "role": "Required", "role_reason": "Required to avoid inferring a confirmed analysis for a particular contrast from a model category or post hoc label.", "application_exception": "Do not silently correct the original printed Turkey to Tukey.", "criterion": "Distinguish the reported ANOVA/mixed models from unverified contrast-specific plans.", "basis": "M08 §8.2.2, M15 §15.3.1; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Prespecify the model, covariates, main/sensitivity analyses and handling of multiple comparisons for each contrast, and report whether the original printing was corrected." }, { "item_id": "N22", "question_type": "Variance and clinical importance", "question": "Were SD, SE, CI and an important difference in MCI verified?", "needed": "Original baseline/change/endpoint means, type of dispersion, CI and the applicable MCI/scale/between-group MCID", "role": "Required", "role_reason": "Required to avoid deciding precision and clinical meaning from significance, trial count or total n alone.", "application_exception": "Do not import another scale's MCID or a generic d = 0.2.", "criterion": "Link the verification level of dispersion, intervals and an important difference to the reasons interpretation is not possible.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Establish evidence for an important difference appropriate to the scale, and report the actual between-group effect, CI and type of dispersion together with denominators." }, { "item_id": "N23", "question_type": "Lead on a nonsignificant monotherapy result", "question": "Was the review's description of a nonsignificant B12 monotherapy result counted as an original result?", "needed": "The S13 citation concerning nonsignificant monotherapy and the original monotherapy table/CI and denominators", "role": "Required", "role_reason": "Required to preserve a contrary lead without promoting the review to verification of original monotherapy numbers.", "application_exception": "Do not turn nonsignificance into an effect of 0, equivalence or established absence of effect.", "criterion": "Distinguish a review lead from an interpretation of no difference that has not been verified in original material.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Disclose the complete original monotherapy comparison results, CIs and reporting selections to compare positive and nonsignificant results using the same criteria." }, { "item_id": "N24", "question_type": "Directness of the older diabetic population", "question": "Can Kwok2017, with 271 participants, be used as an independent result for clinical MCI?", "needed": "Definition of the clinical MCI stratum, its separate main global cognition result and original denominator/interval", "role": "Required", "role_reason": "Required to avoid substituting a mixed nondemented diabetic population and CDR 0.5 for a confirmed MCI stratum.", "application_exception": "Do not exclude a study with an actual B12 monotherapy arm on ingredient grounds.", "criterion": "Use only the verified scope of direct comparisons in the whole cohort and a separately identified MCI stratum.", "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; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Prespecify the clinical MCI stratum and report its monotherapy comparison and main global score/CI separately." }, { "item_id": "N25", "question_type": "Combination treatment in MCI and 24 months", "question": "Does Kwok2020, with 279 participants and CDR-SOB at 24 months, provide a result for B12 alone?", "needed": "Composition of the methylcobalamin/folic acid arm, original CDR-SOB results at 24 months and a contrast differing only in B12", "role": "Required", "role_reason": "Required to avoid attributing a multiple-ingredient effect to B12 alone merely because the MCI population matches.", "application_exception": "Preserve the combination treatment's original result and duration without decomposing them into monotherapy-arm numbers.", "criterion": "Even within MCI, distinguish multiple active ingredients and a different primary endpoint.", "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 §3.2.3, M08 §8.2.2–8.2.3; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Design a contrast differing only in B12 on the same background, and prespecify the effect of interest on the global scale." }, { "item_id": "N26", "question_type": "Deficiency, mixed cognitive status and an unfavorable domain result", "question": "In Eussen2006, what is the scope of the 195 participants and the memory result favoring placebo?", "needed": "Separate clinical MCI stratum/main global result, original memory-domain table and DOI identity", "role": "Required", "role_reason": "Required to distinguish biochemical deficiency, mixed cognitive status and domain results.", "application_exception": "An actual B12 monotherapy arm exists; do not exclude the study because it also has a combination arm.", "criterion": "Preserve the deficient population with mixed cognitive status and the domain result favoring placebo within their original scope.", "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; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Separate the monotherapy contrast in clinical MCI, and report global cognition and the memory domain in separate plans/results." }, { "item_id": "N27", "question_type": "Mixed routes, two chemical forms and printed inconsistencies", "question": "Were the routes and printed dose/dropout inconsistencies in Zhou2023 distinguished?", "needed": "Dose unit, route/chemical form, flow diagram, dropout-rate table and corrections in the original Methods", "role": "Required", "role_reason": "Required to avoid turning injection followed by two oral chemical forms in broad cognitive impairment into oral monotherapy in MCI.", "application_exception": "Do not arbitrarily correct the printed 500 mg unit or dropout-rate inconsistencies recorded by the original review to another unit or value.", "criterion": "Link only the boundaries of the mixed regimen and the currently retained record of inconsistencies.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Compare units and dropout flow in the original tables/Methods, and separately design an oral single-chemical-form contrast in clinical MCI." }, { "item_id": "N28", "question_type": "Uncontrolled before-and-after results and inconsistent counts", "question": "In Jatoi2020, are the before-and-after MMSE responses in 202 participants a between-group effect?", "needed": "Control/allocation, original MMSE response table/participant counts and definition of the deficient population", "role": "Required", "role_reason": "Required to distinguish before-and-after improvement after correction of deficiency from efficacy versus placebo.", "application_exception": "Preserve inconsistent counts in the original abstract without reconstructing detailed subgroup counts absent from the current material.", "criterion": "Specify the limitations of uncontrolled before-and-after results and inconsistent participant counts.", "basis": "M08 §8.1–8.2.3; internal application; M08 §8.2.2, 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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Use an appropriate control on the same background, and report the clinical MCI population and global-scale effect with denominators/intervals." }, { "item_id": "N29", "question_type": "VITACOG combination, imaging and the same family", "question": "Were the 271 participants and subsequent imaging reports from VITACOG counted as independent monotherapy replications?", "needed": "VITACOG registration/report family and linkage of the three active ingredients to original/subsequent endpoints", "role": "Required", "role_reason": "Required to avoid double-counting combined B vitamins and subsequent reports from the same trial as B12 monotherapy replications.", "application_exception": "Retain the original imaging and cognition reports without creating separate independent trial counts.", "criterion": "Distinguish the B12/folic acid/B6 combination contrast from imaging within the same trial family.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; 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; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Link overlapping participants by trial family, and separately design/analyze the B12 monotherapy contrast and main global cognition outcome." }, { "item_id": "N30", "question_type": "Alzheimer's disease and combination treatment", "question": "Was Chen's combination trial in Alzheimer's disease used as a monotherapy effect in MCI?", "needed": "Alzheimer's disease population, folic acid/B12 composition, original n/endpoints and a separate MCI contrast", "role": "Required", "role_reason": "Required to avoid extending material differing in both diagnosis and ingredients to a direct effect in MCI.", "application_exception": "If the original n is absent from the current material, do not fill it in with participant numbers from another study.", "criterion": "Preserve the AD/combination boundaries and unverified original numbers within their original scope.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Separately design a comparison in clinical MCI differing only in B12, and distinguish it from AD results." }, { "item_id": "N31", "question_type": "Adjacent monotherapy trial and historical access failure", "question": "Were unverified original numbers from Dangour2015 used as current direct evidence?", "needed": "Original population, dose, denominator/global scale and the main result in the clinical MCI stratum", "role": "Required", "role_reason": "Required to distinguish a discovered RCT bibliographic record from an unobtained full text and unavailable population details.", "application_exception": "Do not label historical full-text access failure as a failure in this exercise, or turn failure to obtain material into absence of research.", "criterion": "Distinguish bibliographic discovery from unverified direct material.", "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; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Assess eligibility after obtaining original population/endpoint/separate-stratum material, and design a clinical MCI monotherapy contrast if needed." }, { "item_id": "N32", "question_type": "Healthy athletes and a recent lead", "question": "Was the 2026 cyclist study extrapolated to clinical MCI?", "needed": "Original population/results, whether clinical MCI was present and bibliographic identity", "role": "Required", "role_reason": "Required to avoid extending an effect in another population to MCI merely because it is a recent cognitive-performance study.", "application_exception": "Retain the bibliographic lead without generating an original n or effect size in this exercise.", "criterion": "Distinguish the amateur-cyclist title from the clinical MCI question.", "basis": "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Separately review/design the monotherapy comparison in clinical MCI, without pooling it with performance results in athletes." }, { "item_id": "N33", "question_type": "Reviews as maps and unverified identity", "question": "Were review averages or the 2025 lead counted as direct monotherapy estimates?", "needed": "Included-study tables, original identities and separate estimates for MCI/monotherapy/global outcomes in the reviews", "role": "Required", "role_reason": "Required to avoid promoting a broad B-vitamin/cognition review to a narrow MCI monotherapy effect.", "application_exception": "Preserve the reviews' negative/positive leads and access limitations without describing the search as complete.", "criterion": "Distinguish the actual mapping roles of S11/S12/S13/S20 from the unverified status of original values.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Link included studies and original contrasts by family, and separately organize only material meeting the same direct criteria." }, { "item_id": "N34", "question_type": "Overlap of reports and trial families", "question": "Were the 21 reports counted as unique independent monotherapy trials?", "needed": "Relationships among Ma/registration/author abstracts, Kwok registration and the VITACOG follow-up family", "role": "Required", "role_reason": "Required to avoid double-counting abstracts, bibliographic records, registration, reviews or subsequent reports of the same Ma2019 study as independent replications.", "application_exception": "Retain provisional linkages/unverified status for families lacking sufficient identity material.", "criterion": "Link report-specific roles and family IDs, and leave the unconfirmed count of unique direct trials blank.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Link each report to a unique trial and its original contrast/timepoint to separate duplication before assessing replication." }, { "item_id": "N35", "question_type": "Current scope and historical verdict", "question": "Were 0 directly eligible results distinguished from the existence of human research?", "needed": "Original evidence date, existence of human research/direct eligibility status, original grade/score and explanation of the historical calculation", "role": "Required", "role_reason": "Required to avoid turning unverified information in the current scope into worldwide absence of research or an effect of 0.", "application_exception": "Preserve the original no_human_study=false and stage-gate projection without rerunning the legacy calculator.", "criterion": "Distinguish the scope as of 2026-09-16 from the reading for conversion on 2026-10-05 and from the original verdict.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "If the original search/eligibility record is updated, disclose the direct criteria for population, ingredient, outcome and duration, together with exclusion reasons." }, { "item_id": "N36", "question_type": "Extension to clinical events and surrogate measures", "question": "Does the global score also answer questions about conversion to dementia, daily functioning and brain atrophy?", "needed": "Separate direct results and interpretive scope for events/daily functioning and the global scale", "role": "Supplementary; required for extending the claim to clinical events", "role_reason": "Considered to distinguish the cognitive-performance objective from separate event/functional and biochemical outcomes.", "application_exception": "Do not unconditionally require a dementia-conversion trial for the global-score question.", "criterion": "Do not substitute global FSIQ, domain tests, brain volume, blood B12/homocysteine or dementia for one another.", "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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "When separately planning claims about conversion to dementia, daily functioning or quality of life, design direct measurements of the corresponding events/functions." }, { "item_id": "N37", "question_type": "Core trial adverse events and denominators", "question": "Were AE, SAE, discontinuations, deaths and observation periods by arm verified?", "needed": "Definitions, collection, participant/event counts, denominators and follow-up periods for AE/SAE and discontinuations/deaths by arm", "role": "Supplementary; required for safety interpretation", "role_reason": "Required to avoid turning unreported adverse events into 0 events or established safety.", "application_exception": "Retain gaps in harms data despite unverified efficacy data, and limit the nonreporting statement to the original abstract's scope.", "criterion": "Distinguish the core candidate's actual harms counts from the unverified scope.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Define and systematically collect adverse events, and report exposed participants, participant/event counts, duration and discontinuations by arm separately from efficacy denominators." }, { "item_id": "N38", "question_type": "UL and nutrition/medication context", "question": "Was the absence of an established UL interpreted as unlimited safety or efficacy in MCI?", "needed": "Original ODS context for UL/medications and safety exposure data by population/formulation", "role": "Supplementary", "role_reason": "Considered to avoid extending nutritional information to clinical efficacy or a guarantee of overall safety.", "application_exception": "Distinguish historical descriptions of official documents from direct reading in this exercise.", "criterion": "Retain the limited role of the absence of an established UL and of the metformin/gastric-acid-inhibitor context.", "basis": "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Design observations of long-term/high-dose exposure and safety by population/formulation, and track concomitant medications and B12 status." }, { "item_id": "N39", "question_type": "Cobalt warning and chemical-form scope", "question": "Was the MHRA warning transferred to the incidence for another B12 chemical form?", "needed": "Original hydroxocobalamin/cyanocobalamin warning and exposure/population/event denominators", "role": "Supplementary", "role_reason": "Required to distinguish the warning's actual chemical-form scope from event incidence.", "application_exception": "General cobalt-allergy prevalence is not an adverse-event rate during B12 treatment.", "criterion": "Preserve the sensitivity warning only for the specified chemical forms, without estimating comparative risks for other chemical forms.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Develop appropriate observational material tracking chemical-form-specific exposure, sensitivity-event definitions and denominators." }, { "item_id": "N40", "question_type": "Injection labeling and Leber/hypokalemia", "question": "Was cyanocobalamin injection labeling repurposed as risk in oral treatment for MCI?", "needed": "The actual injectable product's labeling warnings about Leber disease and hypokalemia during intensive treatment of severe anemia, and direct oral safety data", "role": "Supplementary", "role_reason": "Required to avoid transferring labeling with a different route, chemical form and intensive-treatment population to incidence in an oral trial.", "application_exception": "Retain the labeling language without interpreting it as incidence for another chemical form or oral treatment in MCI.", "criterion": "Distinguish the population/route in injection labeling from the current oral question.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing 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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Separately observe safety counts in the oral MCI population by formulation, exposure and medical history, distinguishing them from intensive injectable-treatment data." }, { "item_id": "N41", "question_type": "Long-term safety and vulnerable populations", "question": "Were harms from high doses or in special populations beyond 6 months verified?", "needed": "Exposure and follow-up for long-term/high-dose use, pregnancy/lactation/children and liver/kidney status", "role": "Supplementary; required for the corresponding extension of safety claims", "role_reason": "Required to avoid extending material from a limited duration/population to overall safety.", "application_exception": "Do not require every rare-harm study for the current cognitive-score question.", "criterion": "Distinguish the direct observation period from the scope of unverified special populations.", "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", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Systematically collect population-specific harms in exposure registries/observational material with sufficient follow-up, and distinguish rare-event reports from incidence." }, { "item_id": "N42", "question_type": "Funding, product provision and independence", "question": "Were unverified Ma funding and disclosures in adjacent trials/reviews distinguished?", "needed": "Original disclosures of Ma funding, product provision, employment/patents/interests and sponsor roles", "role": "Supplementary; required for a claim of independence", "role_reason": "Required to avoid transferring disclosures from adjacent material as verification of the core trial's funding or independence.", "application_exception": "Do not automatically discard results because industry-related support exists, or treat a declaration of no sponsor role as establishing absence of bias.", "criterion": "Distinguish unverified core material from the actual scope of VITACOG/S13 disclosures.", "basis": "Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application", "condition_origin": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "Transparently report the core trial's funding, product provision and author relationships, and separately assess replication criteria for unique trials." }, { "item_id": "N43", "question_type": "Material type, reading and access dates", "question": "Was summary reading separated from historical/current access for the 21 sources?", "needed": "Bibliographic/original URLs by material type, historical access level, access date and exact locations actually read in this exercise", "role": "Required", "role_reason": "Required to avoid retrospectively treating the prior manuscript's reading level and original review date as successful access/full-text reading in this exercise.", "application_exception": "If there is no actual access-date field, leave it blank and do not substitute verified_date for the access date.", "criterion": "Record reading of the current stored summaries, external access not attempted/material not read, and historical descriptions separately.", "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": "Individual internally designed criteria/model review with the retained case known. This is not clinical preregistration or independent methodological certification.", "proposed_research": "When direct material is subsequently obtained, record type, acquisition/access/reading/date and exact location as separate events, and review linked rows again." } ] }