{ "title": "Nicotinamide riboside (NR; NIAGEN capsules, exact salt and batch unverified) × Improvement in 10-week change in MoCA total score in older adults with clinical MCI", "criteria_version": "NGM-v3094-ORAL-NIAGEN-MCI-MOCA-REPORTED10W-1.1", "criteria_date": "2026-10-05", "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 conditions, and reasons for changes, and distinguish variations in interventions.", "review_level": "Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool." }, { "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 studies from reports and link them; do not exclude a study solely because its results are unreported.", "review_level": "Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool." }, { "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": "Fix the outcome and effect of interest when reviewing randomization, deviations, missingness, measurement, and selective reporting.", "review_level": "Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool." }, { "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. Precision is not determined by sample size alone.", "review_level": "Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool." }, { "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 those for efficacy. Case reports do not establish incidence rates.", "review_level": "Reuse of existing 1585 method copies and historical principles. Not a new review of the full methodological texts or implementation/certification of an official tool." } ], "status_dictionary": { "Met": "The identity, values, and attribution/interpretation boundaries for this condition were verified in the archived materials. This is separate from clinical sufficiency or certification.", "Partly verified": "Some materials have been linked, but details, directness, and comparison remain to be resolved.", "Unverified": "The necessary materials/values are unverified within the preserved scope that was read. This does not mean no effect, 0 events, or an incomplete production review.", "Conflicting records": "The original discrepancy/ambiguity within the same item is retained without arbitrary correction.", "Not applicable": "An extension requirement outside the narrow assessment target does not apply. This differs from insufficient materials or materials not read.", "Not applicable (alias)": "Alias for the gray display of Not applicable.", "Not read": "External materials have not been directly read this time. This is separate from reading the currently archived summaries.", "Review incomplete": "The individual review for preparation of the table remains unfinished. This is separate from unverified materials." }, "schema_version": "chamgap-public-criteria-1.0", "condition_origin": "Chamgap’s own application conditions", "requirements": [ { "item_id": "N01", "question_type": "Independent question", "question": "Which single MoCA comparison is being tabulated?", "needed": "The current claim under assessment, the identity of the assessment question, facets, subclaims and canonical URL.", "role": "Required", "role_reason": "Needed to avoid combining general cognitive function or multiple endpoints into a single effect for this question.", "application_exception": "subclaims is an empty array. Do not automatically create questions about RBANS, dementia events, gait speed or other B3 forms.", "criterion": "Fix the direction of change in MoCA total score for clinical MCI, age 65 years or older, oral NIAGEN with NR as the single active ingredient, dose escalation, a reported 10-week course and placebo.", "basis": "Question-clarification principles in M03 §3.1 and §3.2.1–3.2.4; detailed separation rules are designed specifically for this review — a specific adaptation for the independent question. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare included materials against an eligibility table for population, intervention, comparator, scale and timing, then examine each to determine whether it addresses the same question." }, { "item_id": "N02", "question_type": "Trial family", "question": "Have Orr’s five reports been linked as one direct trial family?", "needed": "DOI, PMID and NCT for each report, and the original evidence field’s family_id and direct-eligibility/replication flags.", "role": "Required", "role_reason": "Needed to avoid counting the article, publisher page, index, PMC and registry as five independent trials.", "application_exception": "Preserve the original direct_trial_family_count=1, without newly summing unique trials or total participants across all registrations.", "criterion": "Group S01–S05 with the same DOI/PMID/NCT as F01, and separate the adjacent F02/F03 studies and candidate registrations from direct replications.", "basis": "Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an application developed for this review; M04 §4.6.1–4.6.2, M15 §15.3.1; application developed for this review — a specific adaptation for trial families. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Cross-check duplicate reports using a linkage table for identifiers, populations, durations and scales, and leave any new family identities unresolved." }, { "item_id": "N03", "question_type": "Reading history", "question": "Has reading the summaries in this review been distinguished from external access at the time?", "needed": "Original URLs, material types, access_level, locator and accessed, and records of copies actually obtained and reading events.", "role": "Required", "role_reason": "Needed to avoid treating a historical full_text record or the existence of a link as full-text reading in this review.", "application_exception": "S03’s prior reuse/lack of an obtained body and S04’s access failure at the time are not current failures. The accessed entries for 12 citations do exist and are preserved.", "criterion": "Distinguish reading the currently archived summary in its original bytes, the per-citation 2026-09-15 access records, and external access not attempted/materials not obtained/not read in this review.", "basis": "Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are designed specifically for this review; M04 §4.5, §4.6.3; limits on the current conversion of materials derive from the user’s scope and this review’s design — a specific adaptation for reading history. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "When materials are actually obtained later, separately record their bytes, format, native location, access dates and reading dates, and cross-check them against the summary links." }, { "item_id": "N04", "question_type": "MCI selection", "question": "What are the clinically defined MCI population and eligibility boundaries of the direct trial?", "needed": "Recruitment pathways, MCI diagnostic procedures, baseline function, inclusion/exclusion criteria and the actual population distribution.", "role": "Required", "role_reason": "Needed to avoid substituting results from healthy aging, dementia or frailty populations for the MCI MoCA comparison.", "application_exception": "Do not infer that the MoCA criterion for newly evaluated candidates was the same diagnostic procedure for every TARCC participant.", "criterion": "Link age 65 years or older, TARCC or PI diagnosis, MoCA<26 with preserved ADL/IADL for newly evaluated candidates, and exclusion of confounding factors.", "basis": "M03 §3.2.1; detailed population conditions are designed specifically for this review — a specific adaptation for MCI selection. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Cross-check eligibility tables by diagnostic pathway and examine the scope of application of baseline function, age and exclusion criteria." }, { "item_id": "N05", "question_type": "Subtype and nutritional status", "question": "Are MCI subtype and baseline nutritional status known?", "needed": "Definitions of MCI subtypes, baseline nutritional testing, sex/status distributions and prespecified subgroup plans.", "role": "Supplementary; required for extension to the relevant stratum", "role_reason": "Needed to avoid automatically transferring effects of deficiency correction or amnestic-MCI trials to the direct population.", "application_exception": "Do not fill unverified nutritional status with either normal status or deficiency. AD biomarkers not being required does not mean biomarker negativity.", "criterion": "Record the actual extent of verification for amnestic subtype, AD biomarkers, nutritional status, selection based on deficiency, and sex strata.", "basis": "M03 §3.2.1; detailed population conditions are designed specifically for this review; M03 §3.2.1–3.2.4; details of dose, duration and effect modification are designed specifically for this review — a specific adaptation for subtype and nutritional status. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Classify only studies with obtained status data into diagnostic/nutritional strata, and cross-check whether interaction analyses were prespecified." }, { "item_id": "N06", "question_type": "NR identity", "question": "Have the actual NR salt, batch and basis for the active amount been verified?", "needed": "Evidence of trial-batch composition, the exact salt/active-amount basis, manufacturing source, and quality/release-profile data.", "role": "Required", "role_reason": "Needed to avoid using the brand or NR name to copy the chemical form, mass or effects of other formulations.", "application_exception": "Do not use EFSA’s NR chloride as the trial’s verified salt, and distinguish it from nicotinamide, niacin, NMN and NAD/NADH.", "criterion": "Link NIAGEN with NR as its single active ingredient, and the exact salt, crystal form, source, purity, batch and basis for the labeled amount, separately.", "basis": "M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review — a specific adaptation for NR identity. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Individually compare the salt, active amount, excipients and purity in trial product/batch materials against the label; do not perform unsupported conversions." }, { "item_id": "N07", "question_type": "Route and capsules", "question": "Have the oral capsules and supplied products been linked to the actual trial?", "needed": "Trial product labels, capsule strength, administration route and evidence of placebo composition/excipients.", "role": "Required", "role_reason": "Needed to avoid combining intravenous preparations, NR combination products or unverified placebo composition with a trial of oral NR as the single active ingredient.", "application_exception": "A single active ingredient does not mean that all excipients have been verified. Do not import formulations of other B3 forms.", "criterion": "Distinguish capsules with NR as the single active ingredient, the oral route, ChromaDex-supplied NR/placebo and unverified excipients.", "basis": "M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review — a specific adaptation for route and capsules. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Code each product’s active ingredient, excipients and route separately, and cross-check the actual trial batch and administration records." }, { "item_id": "N08", "question_type": "Escalation and actual dose", "question": "Has the target dose been distinguished from weekly escalation and individual modifications?", "needed": "Weekly dosing schedules, medication-taking records, adherence/discontinuation/dose reductions by arm, and records of exposure to the target dose.", "role": "Required", "role_reason": "Needed to avoid turning the 1000 mg target into every participant’s actual dose throughout the entire period.", "application_exception": "A specified target capsule count does not prove that capsules were taken on every actual date. Do not recalculate or convert to equivalent doses.", "criterion": "Link the 250→500→750→1000 mg/day escalation, the target of 500 mg 2 times daily and actual modifications for tolerability.", "basis": "M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review; M03 §3.2.3, M08 §8.2.2–8.2.3; application developed for this review — a specific adaptation for escalation and actual dose. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare planned dosing schedules against individual adherence and dose-reduction records to examine the difference between the effect of assignment and actual exposure." }, { "item_id": "N09", "question_type": "Dosing-duration conflict", "question": "Do the reported 10 weeks and the durations stated for each stage agree?", "needed": "The original dosing schedule, explanations/corrections for the text and figure, and individual dates and target-dose exposure data.", "role": "Required", "role_reason": "Needed to avoid arbitrarily adding different schedule descriptions to create a new total duration.", "application_exception": "Do not resolve ambiguities in the text/figure by substituting a new 9-week duration or a confirmed 10-week target-dose period.", "criterion": "Preserve separately the overall 10 weeks, the stages in the text, and Figure 1’s final 1 g for 6 weeks, leaving the exact number of days unverified.", "basis": "M03 §3.2.2–3.2.3; reverse labeling and adaptations of checks are designed specifically for this review; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is designed specifically for this review — a specific adaptation for the dosing-duration conflict. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Cross-check the reference visits and the start/end of each stage in the original schedule, and link author explanations/corrections with actual dosing dates." }, { "item_id": "N10", "question_type": "Assessment interval", "question": "Have the MoCA visit labels, actual individual assessments and intervals from the last dose been verified?", "needed": "Actual dates of each assessment, intervals between the last dose and assessment, and visit schedules/allowable windows.", "role": "Required", "role_reason": "Needed to avoid using the treatment duration as the exact interval between the two score measurements.", "application_exception": "Study week numbers are not individual elapsed days or intervals after the last dose.", "criterion": "Distinguish Figure 1’s visits at study weeks 1 and 13 from the reported 10-week dosing period, and record the extent of verification of actual assessment dates, visit windows and intervals after the last dose.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are designed specifically for this review; M08 Table 8.2.a, M03 §3.2.4; application developed for this review — a specific adaptation for the assessment interval. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Cross-check visit, dosing and assessment timelines separately to verify the actual measurement window for the selected change score." }, { "item_id": "N11", "question_type": "Placebo and concomitant treatment", "question": "Have the comparator arm, common care and changes been verified?", "needed": "Detailed inventories of placebo/usual medications, diet, treatments, changes and adherence in both arms, and their handling in the analysis.", "role": "Required", "role_reason": "This is needed to avoid attributing the effects of add-on therapy to cognition drugs or other concurrent interventions to NR.", "application_exception": "The absence of a description of prescribed exercise/cognitive training in the reviewed main text does not mean that all concomitant interventions were absent.", "criterion": "Distinguish ChromaDex placebo and actual concomitant interventions/exclusions, adherence and rescue interventions/changes from the contrast based on assignment to NR.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are custom-designed; M03 §3.2.3, M08 §8.2.2–8.2.3; custom application — item-specific adaptation for placebo and concomitant interventions. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare records of concomitant interventions, medication changes and adherence in both arms to review the actual comparison of interest and their effects on the analysis." }, { "item_id": "N12", "question_type": "Allocation and concealment", "question": "Have allocation and concealment in the actual parallel RCT been verified?", "needed": "Random sequence generation/concealment procedures, allocation lists, baseline tables, the protocol and explanations of subsequent exclusions.", "role": "Required (causal efficacy)", "role_reason": "This is because the RCT label alone cannot establish that all problems in the allocation process have been resolved.", "application_exception": "Do not describe unverified allocation concealment as not performed. Requirements for handling crossover/cluster designs do not apply to the direct parallel trial.", "criterion": "Compare sequence generation, concealment, baseline balance and subsequent exclusions in the randomized double-blind placebo-controlled pilot.", "basis": "M08 §8.1–8.2.3; custom application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed — item-specific adaptation for allocation and concealment. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare procedures before allocation and exclusions after allocation in chronological order, and review the limitations they impose on the effect of interest." }, { "item_id": "N13", "question_type": "MoCA measurement", "question": "Have the scale version, assessment blinding and repeated measurements been verified?", "needed": "Records of the MoCA version, language, education adjustment, alternate forms/assessment procedures and assessor blinding.", "role": "Required", "role_reason": "This is needed to avoid treating the scale name and the trial's double-blind description as proof that the actual testing procedures were fully identical.", "application_exception": "Unverified test details do not establish that MoCA was not used or that measurement bias is confirmed.", "criterion": "Compare the MoCA total score, score direction, version/language/education adjustment, assessor blinding and measurement conditions in each arm.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M08 Table 8.2.a, M03 §3.2.4; custom application — item-specific adaptation for MoCA measurement. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare the version, assessors, education adjustment and repeat-testing conditions across arms, and review the actual measurement limitations." }, { "item_id": "N14", "question_type": "Endpoint hierarchy", "question": "Has alignment of the article's outcome hierarchy and statistical objectives with the prospective registration/SAP been verified?", "needed": "The article's outcome hierarchy and statistical section, initial registration/amendment history, protocol and SAP.", "role": "Required", "role_reason": "This is needed to avoid automatically equating the article's primary designation with a prospective plan for confirmatory between-group efficacy testing.", "application_exception": "Do not turn failure to obtain the original registry record into a conclusion of nonregistration or confirmed selective reporting.", "criterion": "Link the safety/tolerability purpose, the article's MoCA primary (1st) outcome and the primary statistical objective of within-NR estimation, and separately verify whether the initial/amended registration and SAP align with the actual reporting.", "basis": "M08 Table 8.2.a, M04 §4.6.3; custom application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed — item-specific adaptation for endpoint hierarchy. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare the endpoints, time points and effects of interest in the initial/amended registration and SAP with the article's hierarchy/analyses, and record differences and their reasons." }, { "item_id": "N15", "question_type": "NR within-arm values", "question": "Have the NR within-arm change/CI and the corresponding analysis denominator, variance and model been verified?", "needed": "Within-arm change, CI definition, model, endpoint-specific n and variance from the original results tables/statistical section.", "role": "Required", "role_reason": "This is needed to avoid relabeling the NR arm's own CI as the CI for the difference in change versus placebo.", "application_exception": "A within-arm before–after CI is not an interval estimating the randomized between-group effect.", "criterion": "Link the NR mean change of −0.30 points and within-arm 95% CI [−2.21,1.61] to a before–after estimate in the same arm, and record the extent to which endpoint n, observed change-score variance and model details have been verified.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M08 §8.2.2, M15 §15.3.1; custom application; M15 §15.3.1–15.3.3; custom application — item-specific adaptation for NR within-arm values. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Code each value in the results tables by arm, time point and statistical measure, and compare within-arm/between-group model outputs." }, { "item_id": "N16", "question_type": "Placebo within-arm values", "question": "Have the placebo within-arm change/CI and the corresponding analysis denominator, variance and model been verified?", "needed": "Placebo results tables, within-arm CI/model definitions, endpoint-specific n and change-score variance.", "role": "Required", "role_reason": "This is needed to avoid constructing a comparative effect by selecting the results of only one arm.", "application_exception": "Do not substitute overlap of the arms' within-arm CIs or a difference in their separate significance findings for a between-group test.", "criterion": "Link the placebo mean change of −0.89 points and within-arm 95% CI [−2.19,0.41] to the placebo arm's own before–after estimate, and record the extent to which endpoint n, observed change-score variance and model details have been verified.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M08 §8.2.2, M15 §15.3.1; custom application; M15 §15.3.1–15.3.3; custom application — item-specific adaptation for placebo within-arm values. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare whether the arms use the same scale, time points and model, and link between-group results as a separate item." }, { "item_id": "N17", "question_type": "Between-group P and historical arithmetic", "question": "Have the reported between-group test, existing arithmetic and formal between-group effect/CI been verified?", "needed": "The reported between-group test, official effect/CI, and records of the inputs, status and direction of existing calculations.", "role": "Required", "role_reason": "This is needed to avoid elevating a positive arithmetic direction to significant improvement or an official between-group estimate.", "application_exception": "Do not recalculate the existing arithmetic based on rounded changes. Do not turn a nonsignificant P into a 0 effect or equivalence.", "criterion": "Distinguish the meaning of between-group P=0.57 from the historical +0.59-point arithmetic, and separately record the actual extent of verification of the formal adjusted between-group effect, CI and denominator/variance.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is custom-designed; M08 §8.2.2, M15 §15.3.1; custom application — item-specific adaptation for between-group P and historical arithmetic. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare the sources and directions of the reported test and existing arithmetic, and link official model effects/CIs separately if available." }, { "item_id": "N18", "question_type": "Effect of interest and analysis", "question": "Have the effect of assignment and the actual analysis population been verified?", "needed": "The SAP, analysis-population definition, handling of post-allocation exclusions/missing data, between-group model and adjustment variables.", "role": "Required", "role_reason": "This is needed to avoid automatically treating the number of completers and the primary within-arm objective as an ITT effect in all assigned participants.", "application_exception": "If the original source does not specify the analysis population, do not fill it in as ITT. Do not impose crossover carryover considerations on the direct parallel trial.", "criterion": "Compare the effect of interest for NR−placebo change with within-arm estimation, the Welch between-group test, the actual analysis population/adjustment and ITT/PP.", "basis": "M08 §8.2.2, M15 §15.3.1; custom application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed — item-specific adaptation for the effect of interest and analysis. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Check the effect of interest, target population, handling of exclusions/adherence and model against the analysis plan and results tables." }, { "item_id": "N19", "question_type": "Baseline tables and ±", "question": "Have conflicting baseline values across tables and the type of ± been distinguished?", "needed": "Original Table 1/3, each table's denominator/scale, the definition of ±, and original corrections/author explanations.", "role": "Required", "role_reason": "This is needed to avoid combining baselines from different tables or assuming that ± is SD/SE to create a new effect/CI.", "application_exception": "The original historical arithmetic C02/C03 is only a record of cross-checks at that time, not a new calculation or resolution of the conflict.", "criterion": "Preserve both arms' baseline/final values in Table 3, the placebo-baseline discrepancy involving Table 1's 24.20, and the unverified meaning of ± separately.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for the specific question are custom-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is custom-designed — item-specific adaptation for baseline tables and ±. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare arms, time points, denominators and definitions of means/variance by table, and review discrepancies for the same item when an original correction is available." }, { "item_id": "N20", "question_type": "Allocation/completion conflict", "question": "Have the 22 assigned participants been distinguished from the 20 in the main text and the 20 completers?", "needed": "The original CONSORT diagram, timing of allocation/exclusions, participant counts by arm and explanations of corrections to the abstract/main text.", "role": "Required", "role_reason": "This is needed to avoid relabeling completers as assigned participants without resolving the conflict between participant-flow stages.", "application_exception": "The original C04 calculation 22−2=20 is a historical check within the participant flow; it neither resolves the textual conflict nor determines endpoint n.", "criterion": "Keep the Figure 2 counts of 22 randomized, 2 MRI-related exclusions and 20 completers separate from the abstract/main-text count of 20 randomized.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed; M04 §4.6.3, M15 §15.3.1–15.3.3; status separation is custom-designed; M08 §8.1–8.2.3; custom application — item-specific adaptation for the allocation/completion conflict. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare allocation, subsequent exclusions and completion in a chronological stage table, and update the conflict only on the basis of author explanations/corrections." }, { "item_id": "N21", "question_type": "MoCA denominator and missing data", "question": "Have the MoCA endpoint analysis denominator and handling of missing data been verified?", "needed": "Endpoint-specific measurement/analysis tables, missing data/exclusions by arm, their handling/SAP and sensitivity analyses.", "role": "Required", "role_reason": "This is needed to avoid substituting the number of completers for the denominator of the score analysis.", "application_exception": "Do not assume that MRI exclusions equal the number with missing MoCA data or fill in an unavailable analysis n.", "criterion": "Link MoCA measurement/analysis n, missing data by arm and reasons for/handling of exclusions separately from allocation and completion counts.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed; M08 §8.2.2, M15 §15.3.1; custom application — item-specific adaptation for the MoCA denominator and missing data. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Check endpoint-specific participant flow, the actual population included in the model and missing-data handling/sensitivity analyses against the source data." }, { "item_id": "N22", "question_type": "Between-group precision", "question": "Can the between-group CI and an applicable important difference be interpreted?", "needed": "The official between-group estimate/CI, observed change-score variance/denominator and evidence on importance appropriate to this population and measure.", "role": "Required", "role_reason": "This is needed to avoid declaring adequate precision or the exclusion of important benefit from sample size, within-arm CIs or nonsignificance alone.", "application_exception": "Planning SD/correlation are not observed variance, and an individual-level MCID is not substituted for a between-group criterion.", "criterion": "Link the between-group CI, observed change-score variance/covariance, denominator and applicable between-group MCID, and preserve their unverified status.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each design are custom-designed; M15 §15.3.1–15.3.3; custom application — item-specific adaptation for between-group precision. No official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare the reported interval with a justified between-group importance criterion; if none is available, leave an interpretive gap. If needed, design a follow-up trial on that basis." }, { "item_id": "N23", "question_type": "Supplement and prospective plan", "question": "Have the ESM DOCX and registry history/SAP actually been compared?", "needed": "ESM 1 DOCX; complete initial/amended registrations; protocol/SAP; official results tables.", "role": "Required", "role_reason": "Needed to prevent the existence of a link from being recast as a completed comparison of the full supplement and prospective plan.", "application_exception": "The direct DOCX URL is absent from the original source, so do not invent it; distinguish the publisher entry link from the unobtained file.", "criterion": "Retain the limits: ESM 1 DOCX was not obtained from the publisher preview, and the prospective plan was not compared using the registry shell/index.", "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 — item-specific adaptation for the supplement and prospective plan. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare actually obtained supplement/registry versions with the article by document identity, date, endpoint, analysis, and time point, and record the reasons for changes." }, { "item_id": "N24", "question_type": "Mechanisms and other measures", "question": "Have NAD, cerebral blood flow, and pTau217 been kept from being recast as MoCA results?", "needed": "Actual measurements, time points, denominators, and analyses for each measure, and material directly comparing them with MoCA total score.", "role": "Required (endpoint boundary)", "role_reason": "Needed to prevent a biological response from being automatically transferred into evidence of improved cognitive scores.", "application_exception": "Retain the current manuscript’s NAD/some cerebral blood flow and pTau217 signals, while adding no brain NAD values that are absent.", "criterion": "Separate mechanisms/biomarkers from clinical functional scales, and preserve positive results under the endpoints actually measured.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M03 §3.2.4; internally defined extension boundary — item-specific adaptation for mechanisms and other measures. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "List each measure separately in the endpoint dictionary, and check whether relationships between changes in a measure and MoCA were prospectively analyzed/directly verified." }, { "item_id": "N25", "question_type": "Wu indirect results", "question": "Are Wu’s population-specific and scale-specific results, and MoCA data matching the fixed question, verified?", "needed": "Wu population composition; crossover/first-block analyses; results by scale; adjustments; duration; trial-family material.", "role": "Required (attribution of indirect evidence)", "role_reason": "Needed to prevent no-difference results or positive signals in other populations/scales from being combined as confirmation/refutation of the same MoCA result.", "application_exception": "The first block and crossover belong to the same F02; they are neither independent replications nor denominators for a direct MoCA analysis.", "criterion": "Preserve the mixed SCD/MCI population, first 8-week/crossover RBANS P=0.55, and adjusted results as recorded, while separately retaining whether they are directly eligible and verified for the fixed clinical-MCI, reported 10-week MoCA result.", "basis": "M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — item-specific adaptation for Wu indirect results. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare populations, scales, durations, analyses, and results before/after adjustment by trial family to distinguish direct eligibility from indirect relevance." }, { "item_id": "N26", "question_type": "Martens indirect results", "question": "Are Martens’s cognitive results and replication data matching the fixed MoCA endpoint and duration verified?", "needed": "Diagnosis; formulation/exposure; duration; results for each cognitive test and their analysis denominators; trial-family identity.", "role": "Required (attribution of indirect evidence)", "role_reason": "Needed to prevent trials with different subtypes, durations, and scales from being numerically pooled as direct MoCA replications.", "application_exception": "Do not use another trial’s denominator as the direct MoCA n. Do not generalize to a lack of effect under all NR conditions.", "criterion": "Preserve NCT03482167’s 12-week amnestic-MCI results on other cognitive scales, and separately retain whether direct replication results matching the fixed MoCA endpoint/duration have been verified.", "basis": "M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; adaptation of outcomes to each question is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — item-specific adaptation for Martens indirect results. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare diagnoses, exposures, scales, time points, and result distributions by study family, and record reasons for inclusion/exclusion for the direct question." }, { "item_id": "N27", "question_type": "Registry candidates", "question": "Are the identities and actual results of other registrations, and their direct relevance to the fixed MoCA comparison, verified?", "needed": "Actual registration text/history, completion/publication, results, and linked reports for NCT04430517, NCT05245903, and NCT05500170.", "role": "Required (scope of verification)", "role_reason": "Needed to prevent registration titles or the existence of studies from being elevated to acquired MoCA results or independent replications.", "application_exception": "Not querying them this time does not establish the absence of results, noncompletion, or nonpublication; retain only the scope of the existing indexed leads.", "criterion": "Preserve the registration/index identities of S10–S12, and distinguish the verified scope of the actual registration histories, results, linked reports, and direct eligibility for the fixed question.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/result 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 §4.5, §4.6.3; limits on the current material conversion follow the user’s scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application — item-specific adaptation for registry candidates. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Link registration/publication identities, and compare populations, formulations, scales, time points, and whether results are public using each actual document." }, { "item_id": "N28", "question_type": "Funding and interests", "question": "Are funding, product provision, author roles, and the scope of independence verification all verified?", "needed": "Reports’ funding, product provision, patents/employment/disclosures and roles, and material linking institutions/trial families.", "role": "Supplementary; required for claims of independence", "role_reason": "Needed to prevent public support alone from being taken to mean no commercial interests, or the same fact from being counted again on a new axis.", "application_exception": "Do not automatically exclude results because interests exist, and do not recalculate the original I1.", "criterion": "Link NIH/VA, ChromaDex, and the known disclosures/roles of Brenner/Orr, while separately retaining the unverified scope of supply/role chains and institutional/trial-family relationships. Do not recast the existence of disclosures as an actual absence of bias.", "basis": "Chamgap’s own independence/attribution conditions. The official-method sections used in this pilot do not vouch for all these detailed items — item-specific adaptation for funding and interests. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare disclosures, provision, and roles by trial family, and attach claims of independent funding/replication only within the verified scope." }, { "item_id": "N29", "question_type": "People and events", "question": "Are the numbers of people with AEs and event counts, event definitions/collection, safety denominators, and exposure time verified?", "needed": "Safety tables; exposure/safety-analysis denominators; event definitions/collection; overlapping events; follow-up/exposure time.", "role": "Supplementary; required for comparative harms", "role_reason": "Needed to prevent repeated-event counts from being converted into incidence among people or carried over as efficacy denominators.", "application_exception": "18/21 are event counts, and 7/10 are records of people. Do not create new risk ratios/differences, pooled denominators, or annual incidence rates.", "criterion": "Distinguish NR 7/10 people and 18 events from placebo 7/10 people and 21 events, and retain the actual scope of verification of safety-analysis populations, event overlap, event definitions/collection, and observation/exposure time.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptation is internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application — item-specific adaptation for people and events. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare people/event counts, event overlap, duration, and collection by arm in an event table without personal identifiers to review the scope of reported aggregates." }, { "item_id": "N30", "question_type": "Dose reduction and nausea", "question": "Are the timeline, alternative causes, and assessment material for nausea/heartburn and dose changes verified?", "needed": "Event onset/recovery; dates of dose reduction/return; concomitant medicines/conditions; assessments; discontinuation records.", "role": "Supplementary; required for interpreting harms", "role_reason": "Needed to prevent severe symptoms or temporal relationships from being automatically translated into SAE/confirmed causation or permanent discontinuation.", "application_exception": "The severity described by severe nausea differs from a seriousness classification; do not invent improvement after dose reduction without support in the manuscript.", "criterion": "Preserve the reduction for 1 NR participant from 1000→750 mg/day for 1 week and return to the target dose, and distinguish the verified scope of event dates, recovery, concomitant medicines/conditions, causality/seriousness, and whether discontinuation was permanent.", "basis": "M03 §3.2.2–3.2.3; reverse-direction indicators and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2 design-specific harm questions; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed recording of confounders is internally designed — item-specific adaptation for dose reduction and nausea. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare exposure/event/dose-reduction/return timelines and alternative causes, and separate severity, seriousness, and causality assessments." }, { "item_id": "N31", "question_type": "Conflicting seriousness classification", "question": "Has the conflict between the statement of no serious adverse events and the report of a placebo stroke been preserved?", "needed": "Original event tables; SAE definitions/assessments; course of the placebo stroke; explanations in the text/corrections.", "role": "Supplementary; required for interpreting safety", "role_reason": "Needed to prevent inconsistency in harm records from being recast as an absence of events or a conclusion that NR is safe.", "application_exception": "Do not attribute the placebo stroke to NR causation or newly apply severity/seriousness criteria.", "criterion": "Leave unresolved the seriousness-classification conflict between the original no serious AE sentence and the report of stroke in 1 placebo participant.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; Chamgap’s own interpretive boundary. M19 principles are referenced, without execution of a formal causality tool — item-specific adaptation for conflicting seriousness classification. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare event definitions, arms, and classifications against the text/tables/protocol, and update the conflicting status only through official corrections/explanations." }, { "item_id": "N32", "question_type": "Wu harm signal", "question": "Within what scope is worsening of a pre-existing gait disorder in another trial interpreted?", "needed": "Wu event tables; baseline gait disorder; exposure/onset/recovery; causality assessments; concomitant-treatment material.", "role": "Supplementary", "role_reason": "Needed to prevent signals from different events/trial families from being combined as repeated events in the same direct trial or as confirmed causation.", "application_exception": "Distinguish worsening of a pre-existing condition from new onset of a gait disorder, and do not translate “possible related” as confirmed causation (“caused”).", "criterion": "For F02, separate the 1 event of worsening of a pre-existing gait disorder during NR, an SAE recorded as possible related, from the direct MoCA family.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2 design-specific harm questions; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed recording of confounders is internally designed; M04 §4.6.1–4.6.2; adaptation of harm material is internally designed; Chamgap’s own interpretive boundary. M19 principles are referenced, without execution of a formal causality tool — item-specific adaptation for the Wu harm signal. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Link unique trial-family/event identities, and compare baseline status, exposure, course, alternatives, and the level of the original assessment." }, { "item_id": "N33", "question_type": "eGFR discontinuation", "question": "Are the low-eGFR discontinuation signal and material for reviewing laboratory tests, baseline status, course, and causality verified?", "needed": "Laboratory values/units; baseline renal status; repeat testing; exposure/discontinuation/recovery; concurrent causes; assessments.", "role": "Supplementary", "role_reason": "Needed to prevent discontinuation based on a laboratory value from being elevated to diagnosed NR-induced kidney injury.", "application_exception": "Do not invent low-eGFR values, risk ratios, or event denominators absent from the input.", "criterion": "For F03, preserve the discontinuation of 1 NR participant following a low-eGFR test result, and separately retain the verified scope of the original laboratory value, baseline/repeat testing, course, concurrent causes, and diagnostic/causality material.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2 design-specific harm questions; temporal-relationship details are internally designed; M19 §19.2.2–19.2.4 design considerations; detailed recording of confounders is internally designed; M04 §4.6.1–4.6.2; adaptation of harm material is internally designed; Chamgap’s own interpretive boundary. M19 principles are referenced, without execution of a formal causality tool — item-specific adaptation for eGFR discontinuation. Not official methodological certification.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare laboratory testing, discontinuation, repeat testing/course, and baseline/concurrent causes, and separate the discontinuation decision from clinical diagnosis/causality." }, { "item_id": "N34", "question_type": "GDS nominal result", "question": "Are the nominal GDS P value and data on direction, effect/interval, hierarchy, adjustment, and importance verified?", "needed": "GDS results, denominator/direction, prespecified hierarchy, adjustment, clinical importance, and related plans.", "role": "Supplementary; required for the corresponding mood claim", "role_reason": "This is needed to avoid selecting a significant result on another scale as a positive result for the MoCA question in which improvement was not demonstrated, or treating it as confirmed harm.", "application_exception": "If the original direction, variance, and clinical diagnosis are unavailable in the current input, do not derive an effect magnitude or causality from P alone.", "criterion": "Retain the separate nominal between-group GDS P=0.035 and state the extent to which direction, effect magnitude/interval, denominator, prespecified hierarchy, multiplicity adjustment, and clinical importance have been verified.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptation is internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M19 §19.1.2–19.2.4; internal application — individual adaptation for the nominal GDS result. Not certification of an official method.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare the endpoint hierarchy and analyses before and after adjustment, and record scale changes and clinical events at separate levels." }, { "item_id": "N35", "question_type": "Long-term and official safety assessments", "question": "Are long-term safety and laboratory values verified for the same MCI population, trial formulation, and exposure?", "needed": "Direct MCI data on long-term safety, original liver/kidney laboratory values, exposure, and vulnerable groups, together with the formulation/population/use conditions in official documents.", "role": "Supplementary; required for extension to overall safety", "role_reason": "This is needed to avoid extrapolating a short study or an official use assessment for a different formulation to long-term safety at high doses in MCI.", "application_exception": "Do not use NR chloride from the EFSA documents to fill in the unverified trial salt, or turn an approval/recommendation into personal dosing instructions.", "criterion": "Distinguish the short-term MCI record from EFSA's different conditions for NR chloride use, and state the extent to which long-term harms, original liver/kidney laboratory values, and vulnerable-group data for the same trial formulation, population, and exposure have been verified.", "basis": "M03 §3.2.1; detailed population conditions are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptation are internally designed; M19 §19.1.2–19.2.4; internal application — individual adaptation for long-term and official safety assessments. Not certification of an official method.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare the molecule, dose, population, and exposure duration in regulatory documents and the trial, and separately review any required long-term or vulnerable-group harm evidence using an appropriate follow-up design." }, { "item_id": "N36", "question_type": "Collection and interpretation of harms", "question": "Are complete event collection, exposure/observation denominators, alternative causes, and the scope of causal statements verified?", "needed": "Prespecified safety collection/diagnostic criteria, tables of all events/discontinuations, exposure by group, concomitant treatments/baseline status, follow-up losses, and causality judgments.", "role": "Supplementary; required for the scope of harms", "role_reason": "This is needed to avoid elevating the existence of harm records to complete collection, incidence rates, or safety certification.", "application_exception": "Do not use unverified details of collection to mean 0 events or no other causes. Do not combine families reporting different events as repeated confirmation of the same harm.", "criterion": "Compare all event definitions, collection, exposure/observation denominators, timing, concomitant treatments, and discontinuations/losses in direct and adjacent families, and record whether the current materials verify a signal, a comparison, or causality.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; M04 §4.6.1–4.6.2; adaptation of harm data is internally designed; Chamgap's own interpretive boundary. References M19 principles; not implementation of an official causality tool — individual adaptation for collection and interpretation of harms. Not certification of an official method.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "Compare prespecified event definitions, collection methods, observation/exposure by group, alternative causes, and omissions, and review the boundaries between statements about signals, comparative risks, and causality." }, { "item_id": "N37", "question_type": "Non-applicability of extended comparisons", "question": "Are optimal dose, subgroups, and persistence after discontinuation imposed as mandatory for this question?", "needed": "Randomized dose comparisons, long-term/post-discontinuation follow-up, and prespecified interaction plans needed when such extensions are actually claimed.", "role": "Supplementary; required for extended claims", "role_reason": "This is needed to avoid requiring every extension study for the narrow assessment target or concluding that a dose is optimal from the main effect.", "application_exception": "The current assessment target does not extend to optimal-dose, persistent, or stratum-specific efficacy, so those extension requirements do not apply. Actual exposure and timing for this question remain unverified.", "criterion": "Distinguish the MoCA comparison under the fixed escalation/reported course from questions about direct dose comparisons, long-term persistence, and prespecified subgroups.", "basis": "M03 §3.2.1–3.2.4; details on dose, persistence, and effect modification are internally designed; M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed — individual adaptation for non-applicability of extended comparisons. Not certification of an official method.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "If an extension question is newly proposed, separate it from the original result, prespecify the effects of interest for dose/follow-up/subgroups, and review the corresponding comparative design." }, { "item_id": "N38", "question_type": "Non-applicability of event prevention", "question": "Is an event trial of dementia prevention imposed as mandatory for MoCA change?", "needed": "The relevant event definitions, direct comparisons, and incidence/follow-up data needed when event prevention is actually claimed.", "role": "Supplementary; required for extension to events", "role_reason": "This is needed to avoid extending cognitive-score changes or NAD measures to prevention of clinical events.", "application_exception": "Do not impose a dementia event trial as a prerequisite for a question about a MoCA value. The conditions for a direct MoCA comparison remain mandatory.", "criterion": "Distinguish change in the clinical functional scale MoCA from separate clinical questions about dementia onset, daily functioning, and death.", "basis": "M03 §3.2.4; internally designed extension boundary; 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; question-specific outcome adaptation is internally designed — individual adaptation for non-applicability of event prevention. Not certification of an official method.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "When defining a separate event question, specify the event, follow-up, denominator, and effect of interest, and compare only its direct evidence." }, { "item_id": "N39", "question_type": "Reference dates and original values", "question": "Were the preservation scope, original judgment, and boundaries for subsequent updates maintained?", "needed": "Original evidence/identity, revision policy, grade/score/axes, calculations, document/publication metadata, and actual subsequent evidence/correction records.", "role": "Required (preservation and scope)", "role_reason": "This is needed to prevent table preparation/technical review from being mistaken for a current exhaustive search, a new efficacy/safety grade, or completed public publication.", "application_exception": "The original document quality A and self-review by the same ChatGPT are not independent clinical certification. The source first_published_at is not a date of completed server deployment.", "criterion": "Separate the original evidence reference date of 2026-09-15, the current summary review date, D28/axes/native values, historical calculations, and unverified matters from new update events.", "basis": "M04 §4.5, §4.6.3; limits on the current data transformation follow the user's scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — individual adaptation for reference dates and original values. Not certification of an official method.", "condition_origin": "Conditions developed specifically for this case with knowledge of the currently preserved content. Neither blinded nor preregistered, and not officially certified.", "proposed_research": "For subsequent evidence/corrections, compare the complete pre-change record while distinguishing the event, condition version, observation, and display, and reconsider the question/family boundaries." } ], "language": "en", "translation_date": "2026-11-01" }