{ "schema_version": "chamgap-public-criteria-1.0", "title": "Riboflavin (vitamin B2), reported single-ingredient oral supplementation × 16-week research-visit peripheral cuff systolic blood pressure in hypertensive MTHFR 677TT adults", "criteria_version": "v3123-MTHFR677TT-SBP16W-1.0", "criteria_date": "2026-10-04", "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": "Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/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": "Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/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": "Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/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": "Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/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": "Historical reuse of actual methods HTML copies/SHA from 1585 and the principles at that time. This is not new full-text methods reading or formal application/certification." } ], "status_dictionary": { "Met": "The narrow documentation criteria for identity, endpoint, attribution, family/exclusions and separation of the original verdict from current reading are met. This is not verification of clinical efficacy, safety or external full texts.", "Partly verified": "Some retained reports address the criterion, but verification of the actual original methods, denominators/implementation, precision and access remains outstanding.", "Unverified": "The necessary values/materials cannot be established from the currently retained inputs and the scope of verification at that time.", "Not reported": "Limited to nonreporting in the specific material/section actually read; not extended to the entirety of external full texts.", "Conflicting information": "Limited to sign/rounding discrepancies between the pre/post table and change row in the related S06 ABPM report. Differences in other endpoints/doses/populations are not automatically labeled as conflicts.", "Inaccessible": "Used only when an actual external access attempt failed in this review. External access was unattempted and materials were unread in this review; historical failures are not inherited.", "Review incomplete": "Means that external materials have not been compared in this review or that actual work remains, distinguished from unverified information in materials already reviewed within a defined scope.", "Not applicable": "Not applicable to establishing event/testing/medication-replacement effects or optimal/long-term regimens outside the narrow 16-week cuff SBP question. This does not certify no effect, safety or absence of research." }, "requirements": [ { "item_id": "N01", "question_type": "Independent claim", "question": "Which blood-pressure question does this table address?", "needed": "Current claim identity, source-text pointer, and population/intervention/comparator/endpoint/time-point boundaries", "role": "Required", "role_reason": "This is needed to avoid extending numerical changes in a TT-selected trial to effects on all hypertension or cardiovascular prevention.", "application_exception": "The subclaims array is empty. Do not automatically split the Korean/English manuscripts and related reports into additional tables.", "criterion": "Preserve the exact /ko/effect and link TT, single-ingredient oral B2, placebo/usual care and 16-week cuff SBP as one question.", "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C04: M03 §3.2.1; detailed population criteria are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid extending numerical changes in a TT-selected trial to effects on all hypertension or cardiovascular prevention. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the current identity, population, actual contrast and measurement boundaries to record included and excluded questions." }, { "item_id": "N02", "question_type": "TT selection", "question": "Have TT selection and validation of genotype testing itself been distinguished?", "needed": "MTHFR 677TT selection, assay method, genotype confirmation, HWE assessment and recruitment criteria", "role": "Required", "role_reason": "This is needed to avoid presenting intervention results in the selected TT population as testing accuracy or benefits of genotype screening.", "application_exception": "CC/CT data and testing care pathways are not substitute evidence for the current TT intervention endpoint.", "criterion": "Preserve TT selection while distinguishing unverified assay methods/HWE from non-applicability of the testing-utility question.", "basis": "C04: M03 §3.2.1; detailed population criteria are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid presenting intervention results in the selected TT population as testing accuracy or benefits of genotype screening. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link recruitment and genotype-confirmation procedures to the original methods to review population classification and applicability." }, { "item_id": "N03", "question_type": "Actual population", "question": "To which adults can the predominantly older TUDA population be applied?", "needed": "Original criteria for age eligibility, baseline hypertension, TUDA recruitment, overt CVD exclusion and representativeness", "role": "Required", "role_reason": "This is needed to avoid treating the mean age and recruitment cohort as evidence of representativeness for all hypertensive adults.", "application_exception": "Do not extend this to existing overt CVD, hypertension in pregnancy, CKD/dialysis or healthy normotensive populations.", "criterion": "Preserve the mean age of 69.1 years, TUDA and absence of overt CVD together with unverified exact age eligibility.", "basis": "C04: M03 §3.2.1; detailed population criteria are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid treating the mean age and recruitment cohort as evidence of representativeness for all hypertensive adults. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare inclusion/exclusion criteria and the baseline characteristics table to record population alignment and differences in applicability for the current question." }, { "item_id": "N04", "question_type": "Mixed treatment-status population", "question": "Can this be described as an effect only in people receiving medication?", "needed": "Treatment status by arm, antihypertensive medication history, treated/untreated denominators and separate between-group estimates", "role": "Required", "role_reason": "This is needed to avoid turning the description of most participants being treated into a treated-only effect.", "application_exception": "Do not remove the trial or reattribute its result to all untreated people because a small untreated fraction was included.", "criterion": "Distinguish the main effect in the mixed population from the unverified separate estimates by treatment status.", "basis": "C04: M03 §3.2.1; detailed population criteria are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid turning the description of most participants being treated into a treated-only effect. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare treatment status, arm composition and the presence of prespecified subgroup/interaction analyses and separate estimates." }, { "item_id": "N05", "question_type": "Molecule and product", "question": "Can the trial tablets be equated with FMN/FAD or combination products?", "needed": "Specifications for the riboflavin tablets' chemical form, release profile, manufacturing origin, excipients and product/batch", "role": "Required", "role_reason": "This is needed to avoid converting the reported ordinary single-ingredient tablets into efficacy claims for other chemical forms or combination products.", "application_exception": "Plant part is not applicable, but gaps concerning the chemical certificate and manufacturing origin remain.", "criterion": "Preserve both the report of ordinary single-ingredient tablets and the unverified exact chemical form/product.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid converting the reported ordinary single-ingredient tablets into efficacy claims for other chemical forms or combination products. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link the original product specifications to the original trial, without inferring equivalence between formulations in the absence of direct comparisons." }, { "item_id": "N06", "question_type": "Route and dose", "question": "What route and actual administration regimen does 1.6 mg/day represent?", "needed": "Oral tablets, supplemental amount, administration frequency, meal timing and total dietary/concurrent nutrient intake", "role": "Required", "role_reason": "This is needed to avoid turning a supplemental amount into total intake or personal dosing advice.", "application_exception": "If daily frequency and total dietary intake are absent, do not arbitrarily specify taking it 1 time or fill in a total amount.", "criterion": "Link the oral route described by tablet intake in the registry and pill boxes in the trial to the supplemental amount of 1.6 mg/day.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid turning a supplemental amount into total intake or personal dosing advice. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare administration procedures, frequency, meals and total-exposure records to distinguish the nominal dose from actual exposure." }, { "item_id": "N07", "question_type": "Exposure and adherence", "question": "Whose records do 16 weeks and overall adherence of 99% represent?", "needed": "Individual administration/assessment timing, pill counts, arm-specific adherence and discontinuation/dropout periods", "role": "Required", "role_reason": "This is needed to avoid presenting the planned duration and overall adherence as every participant's actual exposure.", "application_exception": "Do not extend the 16-week result to optimal duration, persistence after discontinuation or long-term effects.", "criterion": "Separate the planned 16 weeks and overall pill-count adherence of 99% from unverified arm-specific/individual information.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / H02: Design-specific harms questions in M19 §19.2; details on temporal relationships are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid presenting the planned duration and overall adherence as every participant's actual exposure. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link administration/visit, returned-pill and arm-specific discontinuation records to review actual exposure and outcome timing." }, { "item_id": "N08", "question_type": "Baseline nutrition", "question": "Can mean EGRac establish that everyone was deficient?", "needed": "Functional B2 status, individual distributions/deficiency criteria, diet, assay interference and effects by deficiency status", "role": "Required", "role_reason": "This is needed to avoid turning group means into individual diagnoses or effects exclusively in deficient participants.", "application_exception": "Deficiency was not a required eligibility criterion, and a population consisting exclusively of nutrient-replete participants is not asserted either.", "criterion": "Preserve the EGRac means with SD and the original ≥1.3 criterion, and leave individual deficiency/separate effects unverified.", "basis": "C04: M03 §3.2.1; detailed population criteria are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid turning group means into individual diagnoses or effects exclusively in deficient participants. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare individual nutritional distributions, assay procedures/interference, total intake and prespecified estimates by deficiency status." }, { "item_id": "N09", "question_type": "Actual comparator", "question": "Have placebo on top of usual care and medication changes been distinguished?", "needed": "Placebo composition/matching, existing antihypertensive medication, actual changes/rescue treatment by arm and the effect of interest", "role": "Required", "role_reason": "This is needed to avoid merging differences in existing treatment or treatment changes into the effect of B2 itself.", "application_exception": "Do not present the existence of background treatment as meaning that its stability was verified.", "criterion": "Link the contrast against placebo on top of usual care with unverified arm-specific medication changes and placebo matching.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid merging differences in existing treatment or treatment changes into the effect of B2 itself. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare original arm-specific concomitant treatments/changes, placebo preparation and the analytical treatment of the effect of interest." }, { "item_id": "N10", "question_type": "Allocation and concealment", "question": "Has implementation of SBP-stratified randomization also been verified?", "needed": "Original methods for the parallel design, stratification, sequence generation, allocation concealment and baseline balance", "role": "Required", "role_reason": "This is needed to avoid presenting allocation issues as resolved solely because of the randomized label.", "application_exception": "Do not convert unverified sequence generation/concealment into nonrandomization or an established magnitude of bias.", "criterion": "Separate the report of SBP-stratified parallel randomization from gaps in sequence generation and concealment implementation.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E01: M08 §8.1–8.2.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid presenting allocation issues as resolved solely because of the randomized label. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link allocation procedures and the baseline table to the selected SBP result to review the level of verification." }, { "item_id": "N11", "question_type": "Blinding", "question": "Are reported blinding and maintained blinding/placebo matching the same verification?", "needed": "Blinding procedures for participants, assessors and laboratory staff; maintenance, placebo matching and arm-specific deviations", "role": "Required", "role_reason": "This is needed to avoid elevating reported blinding to complete verification of its maintenance and measurement independence.", "application_exception": "Do not erase gaps in blinding and implementation solely because cuff measurement is objective.", "criterion": "Record reported participant/assessor/laboratory blinding separately from unverified maintenance/placebo matching.", "basis": "E02: M03 §3.2.3, M08 §8.2.2–8.2.3; self-developed application / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating reported blinding to complete verification of its maintenance and measurement independence. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link who was blinded, the procedures, verification of maintenance and access to assessment data to the original methods." }, { "item_id": "N12", "question_type": "Measurement setting", "question": "Does the office-type classification establish an actual office location?", "needed": "Research visits, A&D UA-787, repeated cuff readings, posture/rest time, physical site and collection procedures", "role": "Required", "role_reason": "This is needed to avoid confusing the measurement classification at research visits with the physical site.", "application_exception": "office-type is a classification based on the research-visit protocol and does not mean a verified office-room.", "criterion": "Preserve reported cuff/repeated measurements and the unverified exact site, posture and rest time.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid confusing the measurement classification at research visits with the physical site. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the measurement protocol, visit procedures, device and averaging method with the original methods/supplement." }, { "item_id": "N13", "question_type": "Endpoint and unit", "question": "Has research-visit SBP been kept separate from other blood-pressure values?", "needed": "Distinction between 16-week SBP, mmHg, the treatment×time contrast and ambulatory/home/central/daytime-nighttime blood pressure", "role": "Required", "role_reason": "This is needed to avoid merging different measures into the same effect because of similar blood-pressure names or durations.", "application_exception": "Do not force DBP or mechanistic/methylation data to serve as substitute endpoints for SBP.", "criterion": "Link the between-group contrast in 16-week research-visit peripheral cuff SBP to the excluded measurements.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid merging different measures into the same effect because of similar blood-pressure names or durations. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare endpoint definitions, time points, units and analysis locations to record attribution by outcome." }, { "item_id": "N14", "question_type": "Denominators", "question": "Are 91 participants and 46/45 participants the actual analyzed denominators?", "needed": "Arm-specific n for allocation, assessment, completion and analysis; flow/exclusions and result-table headings", "role": "Required", "role_reason": "This is needed to avoid turning randomized counts into analyzed n or denominators for CI calculation.", "application_exception": "Do not back-calculate arm-specific n from the historical arithmetic analysis total of 87.", "criterion": "Separate the randomized 91(46/45) from null analyzed arm denominators and the historical arithmetic total.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E01: M08 §8.1–8.2.3; self-developed application / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid turning randomized counts into analyzed n or denominators for CI calculation. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the flow diagram, result tables and original analysis-population records to link actual denominators by outcome." }, { "item_id": "N15", "question_type": "LOCF and missing data", "question": "What analysis does LOCF for 3 dropouts form part of?", "needed": "Dropout arms/reasons/timing, LOCF inputs, missing-data assumptions and alternative analyses", "role": "Required", "role_reason": "This is needed to avoid presenting the use of LOCF as evidence that missing-data issues were resolved.", "application_exception": "Do not newly estimate a definite magnitude of bias or loss of effect from gaps concerning LOCF.", "criterion": "Separate reported LOCF for 3 dropouts from gaps in arm-specific/timing and sensitivity data.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid presenting the use of LOCF as evidence that missing-data issues were resolved. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare dropout flow, last observations, LOCF application and original alternative analyses." }, { "item_id": "N16", "question_type": "Outlier exclusions", "question": "Was the exclusion of 4 participants with SBP outlier values planned in advance?", "needed": "Outlier definition, arm-specific exclusions, advance plans and original analyses/denominators before and after exclusion", "role": "Required", "role_reason": "This is needed to avoid confusing possible post hoc exclusions and the authors' ITT label with an analysis of everyone without exclusions.", "application_exception": "Do not infer fabrication, invalidity or a quantitative magnitude of bias from the exclusion record alone.", "criterion": "Preserve the exclusion of 4 participants as outliers, the unverified prespecified criteria and the difference from ITT without exclusions.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid confusing possible post hoc exclusions and the authors' ITT label with an analysis of everyone without exclusions. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare exclusion criteria and the timing of their planning with the original SAP/flow and analyses before and after exclusion." }, { "item_id": "N17", "question_type": "Effect of interest and analysis", "question": "What estimate does the reported treatment×time difference represent?", "needed": "Original explanation of the treatment×time model, adjustment, effect of interest, ITT/PP definitions and analysis population", "role": "Required", "role_reason": "This is needed to avoid newly establishing a between-group effect of assignment from within-group changes or labels alone.", "application_exception": "Do not arbitrarily relabel the authors' reported ITT as PP or apply a new model.", "criterion": "Link the reported treatment×time between-group comparison to limits on verification of actual analyzed n/exclusions and adjustment.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid newly establishing a between-group effect of assignment from within-group changes or labels alone. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the original model, contrast of interest, denominators and handling of missing data/exclusions with the corresponding SBP result." }, { "item_id": "N18", "question_type": "Group means and SEM", "question": "Are the parenthetical values in Table 3 SD or SEM?", "needed": "Table 3 mean/SEM headings, pre/post time points, analyzed n by arm and the original table", "role": "Required", "role_reason": "This is needed to avoid reusing the standard error of the mean as a between-person SD or change-score SD.", "application_exception": "The SD of nutritional EGRac and the SEM in SBP Table 3 refer to different variables/variance measures.", "criterion": "Preserve each arm's pre/post means(SEM) and the unverified n/change SD exactly as recorded.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid reusing the standard error of the mean as a between-person SD or change-score SD. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the original headings, notes, time points and variance types without performing new variance conversions." }, { "item_id": "N19", "question_type": "Reported effect and P", "question": "Have the favorable reported between-group value and within-group arithmetic been distinguished?", "needed": "Reported between-group estimate with direction normalized, the contrast to which P applies and the original result location", "role": "Required", "role_reason": "This is needed to avoid erasing the favorable result or combining it with within-group changes to create a different effect.", "application_exception": "Do not substitute P=0.033 for a CI, clinical threshold or established effect.", "criterion": "Attribute the reported between-group −5.6 mmHg and P=0.033 to the corresponding 16-week contrast.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid erasing the favorable result or combining it with within-group changes to create a different effect. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the original result text/table, contrast direction and attribution of P, and distinguish them from other arithmetic." }, { "item_id": "N20", "question_type": "± and CI", "question": "Can 5.6±2.6 be read as an exact CI?", "needed": "Variance type of ±2.6 for the overall contrast, exact CI, degrees of freedom/model and analyzed n", "role": "Required", "role_reason": "This is needed to avoid reconstructing a CI from a ± value of unverified type and P or randomized n.", "application_exception": "Do not automatically treat the fact that Table 3 reports SEM as verification that ±2.6 for the overall contrast is an SE.", "criterion": "Preserve the reported overall reduction of 5.6±2.6, the unverified variance type and null CI.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid reconstructing a CI from a ± value of unverified type and P or randomized n. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Obtain the original heading/model output and exact interval for the overall contrast to review precision." }, { "item_id": "N21", "question_type": "Clinical importance", "question": "Does statistical standardization validate a between-group MCID?", "needed": "A justified between-group importance threshold and exact interval appropriate for this population, intervention and 16-week SBP contrast", "role": "Required", "role_reason": "This is needed to avoid substituting statistical conventions or risk relationships from other drugs for a minimum clinically important difference.", "application_exception": "Do not unconditionally require a cardiovascular-event trial for an SBP-change question.", "criterion": "Maintain the null between-group clinical threshold and the separate attribution of the historical approximately −0.286 standardization.", "basis": "E05: M15 §15.3.1–15.3.3; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid substituting statistical conventions or risk relationships from other drugs for a minimum clinically important difference. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Review the applicability conditions of evidence on importance for the selected SBP contrast and link it to the reported interval." }, { "item_id": "N22", "question_type": "Historical arithmetic", "question": "Have −5.5 and the analysis total of 87 been kept from becoming newly reported values?", "needed": "Inputs and attribution of the descriptive arithmetic at that time, and its distinction from reported estimates and denominators", "role": "Required", "role_reason": "This is needed to avoid elevating arithmetic from rounded mean differences and exclusion counts to the authors' causal estimate/actual analyzed n.", "application_exception": "The historical calculation files were not read in this review; values are not recalculated and no CI is added.", "criterion": "Preserve −5.5, −4.7/0.8 and 87 only as original historical arithmetic, and retain −5.6 and arm-specific nulls.", "basis": "C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E04: M08 §8.2.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating arithmetic from rounded mean differences and exclusion counts to the authors' causal estimate/actual analyzed n. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare inputs in the historical arithmetic records and their attribution to original reports/flow to distinguish descriptive values from analysis values." }, { "item_id": "N23", "question_type": "Registration timing", "question": "Did registration occur before recruitment?", "needed": "Recruitment/registration/edit timing for ISRCTN23620802 and the original planning history", "role": "Required", "role_reason": "This is needed to avoid automatically turning retrospective registration into preregistration or nonregistration.", "application_exception": "The existence of an official registration does not replace the full original prospective protocol/SAP.", "criterion": "Preserve the scope of the records for first recruitment on 2010-05-01, registration on 2012-02-02 and the edit on 2015-09-02.", "basis": "C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid automatically turning retrospective registration into preregistration or nonregistration. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare registry versions/change history and recruitment/planning timing with the original results." }, { "item_id": "N24", "question_type": "Analysis hierarchy", "question": "Does a broad blood-pressure primary (1st) endpoint guarantee a prespecified single-SBP hierarchy?", "needed": "Prospective protocol/SAP, SBP hierarchy, time points/subgroups, multiplicity and exclusion plans", "role": "Required", "role_reason": "This is needed to avoid turning a broad registered endpoint into established prespecification of the selected SBP analysis.", "application_exception": "Do not use unverified plans to mean that selective reporting or fabrication has been established.", "criterion": "Distinguish the registry's broad blood-pressure primary (1st) outcome from the unverified single-SBP hierarchy/SAP/multiplicity.", "basis": "E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules. The specific reason for applying this to this case is as follows: This is needed to avoid turning a broad registered endpoint into established prespecification of the selected SBP analysis. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare planned and reported endpoints, time points, analyses/exclusions, multiplicity and reasons for changes." }, { "item_id": "N25", "question_type": "Directly eligible family", "question": "Do 20 sources represent 20 directly eligible trials?", "needed": "Linkage of S01/S02 and related reports to TF01 recruitment and outcomes/time points, and independent-replication data", "role": "Required", "role_reason": "This is needed to avoid summing registrations/reports as trials or independent replications.", "application_exception": "The original count of 1 directly eligible family does not mean 1 study worldwide or the count of all human studies.", "criterion": "Distinguish the single TF01 family from its registry/unacquired companion abstract, and retain the unverified status of replication within the same boundary.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C10: Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all these detailed items / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid summing registrations/reports as trials or independent replications. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link report→family→selected outcome, and review actual independence of recruitment and whether replication falls within the same boundary." }, { "item_id": "N26", "question_type": "CVD follow-up", "question": "Were the existing CVD trial and its 4-year follow-up combined as independent replications?", "needed": "Cohort, genotype and reintervention/follow-up linkage for Horigan 2010/Wilson 2012, and result locations", "role": "Supplementary", "role_reason": "This is needed to avoid counting a different CVD population and follow-up of the same cohort as replications of the current TT trial without CVD.", "application_exception": "Exclusion from the original direct question does not mean that the study had 0 participants or no effect.", "criterion": "Preserve the single TF02 family comprising the initial study/4-year follow-up and its different CVD/mixed-genotype boundary.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C04: M03 §3.2.1; detailed population criteria are self-designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid counting a different CVD population and follow-up of the same cohort as replications of the current TT trial without CVD. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare recruitment, cohort linkage and follow-up/reintervention to record independence and population differences." }, { "item_id": "N27", "question_type": "ABPM conflict", "question": "Have the table/change-row discrepancies in the 10 mg ambulatory blood-pressure abstracts been preserved?", "needed": "Original S05/S06 abstracts, pre/post and change rows, signs/rounding, denominators and registry/participant linkage", "role": "Supplementary", "role_reason": "This is needed to avoid transferring favorable ABPM findings or numerical differences to the selected 1.6 mg cuff SBP question or arbitrarily correcting them.", "application_exception": "The same research network, n 81 and similar dose/duration do not constitute complete verification of independence at the individual-ID level.", "criterion": "Retain TF03's different dose/age/baseline subgroup/measurement and the sign/rounding conflict in S06.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed. The specific reason for applying this to this case is as follows: This is needed to avoid transferring favorable ABPM findings or numerical differences to the selected 1.6 mg cuff SBP question or arbitrarily correcting them. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare original tables/change rows and participant/registry linkages to review the scope of the conflict and the candidate same-family relationship." }, { "item_id": "N28", "question_type": "Biosample reanalysis", "question": "Is methylation reanalysis a new SBP trial?", "needed": "Parent trials, sample/participant linkage, treatment-specific SBP results and access scope for S07/S19", "role": "Supplementary", "role_reason": "This is needed to avoid adding mechanistic analyses of samples from previous trials as new participants or independent SBP effects.", "application_exception": "If the parent family is null, do not assign an arbitrary family or add to the direct-replication count.", "criterion": "Preserve gaps in the parent-cohort mixture for previous-trial blood in S07 and the unacquired candidate S19.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid adding mechanistic analyses of samples from previous trials as new participants or independent SBP effects. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link original sample sources, parent recruitment and analysis results to review new-trial/duplicate/unclear relationships." }, { "item_id": "N29", "question_type": "Gambia plan", "question": "Is the planned dose in the Gambia protocol an actual result?", "needed": "S08 protocol, original NCT03151096 registry, actual recruitment/denominators and results/status", "role": "Supplementary", "role_reason": "This is needed to avoid elevating a plan involving different genotypes and a different deficiency context into an actual replication of the TT trial.", "application_exception": "Do not present the planned 5 mg and 16 weeks as actual administration, measurements, sample/effect.", "criterion": "Preserve the TF04 plan for CC/CT in a different deficiency context and null actual_sample/result.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C04: M03 §3.2.1; detailed population criteria are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating a plan involving different genotypes and a different deficiency context into an actual replication of the TT trial. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare the protocol with actual implementation/original results to record differences in plans, implementation and population." }, { "item_id": "N30", "question_type": "Early and unpublished results", "question": "Does blinded FMD in the thesis abstract answer treatment-specific SBP?", "needed": "S09 thesis, InteRVENE candidate registry and treatment-specific SBP denominators/original results", "role": "Supplementary", "role_reason": "This is needed to avoid turning an early blinded endothelial analysis into a treatment-separated blood-pressure effect or absence of research.", "application_exception": "The planned 2026-10-31 embargo end is metadata from that time; release/current status has not been verified in this review.", "criterion": "Distinguish the abstract's early blinded FMD from null actual SBP effect/sample.", "basis": "C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid turning an early blinded endothelial analysis into a treatment-separated blood-pressure effect or absence of research. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link the access/publication scope of the thesis manuscript, registration and treatment-specific results to review endpoint attribution." }, { "item_id": "N31", "question_type": "Candidate registries", "question": "Have official content and current status been verified from a registry link alone?", "needed": "Full official S16/S17/S18 registries, versions/history, result/recruitment status and report linkage", "role": "Supplementary", "role_reason": "This is needed to distinguish links/discovered candidates from official content actually read.", "application_exception": "Do not present historical API failures/JavaScript shell responses as access failures in this review.", "criterion": "Preserve unverified original registry content and the level of candidate linkage, leaving access to all of them unattempted in this review.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to distinguish links/discovered candidates from official content actually read. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "In an authorized follow-up check, compare official registry versions with original reports/results to review identity." }, { "item_id": "N32", "question_type": "Role of the review", "question": "Have the review's pooled effects been kept from being imported as verification of the original trials?", "needed": "S10 inclusion/exclusion and trial-family discovery, numbers/denominators in each original report and the search cutoff date", "role": "Supplementary", "role_reason": "This is needed to avoid elevating review averages, author correspondence or denominators to facts verified directly from the originals or additional replications.", "application_exception": "Distinguish the review's search end date of 2024-10-24 from the original task's search cutoff of 2026-09-16.", "criterion": "Link S10 only in its discovery/context role, and do not adopt pooled values as new observations.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating review averages, author correspondence or denominators to facts verified directly from the originals or additional replications. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link the review's references/candidate families to original reports to distinguish discovery from direct verification." }, { "item_id": "N33", "question_type": "Observational associations", "question": "Have observations of B2 levels/genotype been kept from becoming effects of additional supplementation?", "needed": "Distinction between the designs, actual exposures, populations and analyses of S14/S15 and oral intervention", "role": "Supplementary", "role_reason": "This is needed to avoid reversing observed level/genotype associations into causal effects of assignment to single-ingredient B2.", "application_exception": "Preserve observational data without assigning new clinical families or issuing genotype-testing recommendations.", "criterion": "Exclude S14 level/genotype associations and S15 retrospective associations from oral B2 intervention evidence.", "basis": "C04: M03 §3.2.1; detailed population criteria are self-designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E01: M08 §8.1–8.2.3; self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid reversing observed level/genotype associations into causal effects of assignment to single-ingredient B2. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare original designs and the exposure→outcome direction to record differences between related association questions and intervention questions." }, { "item_id": "N34", "question_type": "Boundary on extensions", "question": "Do SBP results answer event prevention, testing utility or medication replacement?", "needed": "Direct comparative data on events/testing pathways, medication replacement and dose/duration for each extension question", "role": "Supplementary", "role_reason": "This is needed to avoid extending a surrogate and the main effect in a specific population to health outcomes, testing benefits or an optimal regimen.", "application_exception": "Do not require every extension trial for the narrow 16-week SBP question itself.", "criterion": "Separate the current SBP question from questions about events/testing/medication replacement, optimal dose and long-term persistence.", "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / E09: M03 §3.2.4; self-defined boundary on extensions. The specific reason for applying this to this case is as follows: This is needed to avoid extending a surrogate and the main effect in a specific population to health outcomes, testing benefits or an optimal regimen. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "If an extension question is separately requested, newly define the population, outcome of interest and pathway/comparison, and review direct evidence." }, { "item_id": "N35", "question_type": "Funding and independence", "question": "To what level have public funding, DSM support and related patents been verified?", "needed": "Funding/product provision, DSM employment, patents, declarations of funder roles and the family research network", "role": "Supplementary", "role_reason": "This is needed to avoid presenting mixed funding as independent funding or turning conflicts of interest into evidence of fabrication.", "application_exception": "Do not elevate the authors' statement of noninvolvement to independent verification of actual roles.", "criterion": "Distinguish mixed public/nonprofit and DSM support and employment/patents from the authors' noninvolvement statement.", "basis": "C10: Chamgap's own independence and attribution criteria. The official methods sections used in this pilot do not validate all these detailed items / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid presenting mixed funding as independent funding or turning conflicts of interest into evidence of fabrication. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare declarations, funding sources, product provision and institution/family linkages to record the scope of independence verification." }, { "item_id": "N36", "question_type": "Trial harms", "question": "Have trial-specific AE counts and people/denominators been verified?", "needed": "Arm-specific AE event/person counts, exposure denominators/duration, definitions/collection, severity and reasons for discontinuation", "role": "Required", "role_reason": "This is needed to avoid turning the existence of an efficacy trial and general safety information into 0 events or safety in the trial.", "application_exception": "Do not arbitrarily attribute the 3 dropouts or the 4 participants excluded from the SBP analysis to AEs or absence of AEs.", "criterion": "Preserve unverified trial-specific harm counts, denominators/collection, and distinguish people/events and efficacy denominators.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are self-designed / E10: M19 §19.1.2–19.2.4; self-developed application / H01: M19 §19.1.2–19.2.4; detailed distinctions are self-designed / H02: Design-specific harms questions in M19 §19.2; details on temporal relationships are self-designed / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; self-developed application / H04: M19 §19.1.2–19.2.4; self-developed application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; self-developed application / H09: Chamgap's own interpretive boundary. References M19 principles; no formal causality tool was applied. The specific reason for applying this to this case is as follows: This is needed to avoid turning the existence of an efficacy trial and general safety information into 0 events or safety in the trial. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link original arm-specific AE tables, collection/discontinuation and exposure time to review reporting scope and comparability." }, { "item_id": "N37", "question_type": "General safety materials", "question": "Are the NIH and NHS explanations AE observations from this trial?", "needed": "Material types, populations/doses and access scope of S11/S12/S13, and original trial harms tables", "role": "Supplementary", "role_reason": "This is needed to avoid transferring general nutrition information or migraine information at a different dose into incidence in the 1.6 mg trial.", "application_exception": "Only a search excerpt of S13 was read at that time, and no numerical UL was adopted; all full texts remain unread in this review.", "criterion": "Distinguish general safety background and urine/tear changes at a different dose from the lack of verification of 0 events in the trial.", "basis": "C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C04: M03 §3.2.1; detailed population criteria are self-designed / E10: M19 §19.1.2–19.2.4; self-developed application / H07: M04 §4.6.1–4.6.2; adaptation for harms data is self-designed / H08: M19 §19.1.2–19.2.4; self-developed application / H09: Chamgap's own interpretive boundary. References M19 principles; no formal causality tool was applied. The specific reason for applying this to this case is as follows: This is needed to avoid transferring general nutrition information or migraine information at a different dose into incidence in the 1.6 mg trial. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare official materials' populations, doses and versions/access scope to separate trial observations from general context." }, { "item_id": "N38", "question_type": "Long-term and personal safety", "question": "Do limited 16-week data answer long-term safety or safety in vulnerable populations?", "needed": "Long-term/rare harms, vulnerable populations, concomitant-treatment interactions, actual exposure and suitable safety data", "role": "Supplementary", "role_reason": "This is needed to avoid extending reporting gaps in a limited population/duration to safety in all populations or dosing recommendations.", "application_exception": "Do not make preservation of the narrow SBP result conditional on obtaining all rare-harm data.", "criterion": "Preserve unverified long-term/special-population safety and the exclusion of personal medication-discontinuation/administration advice.", "basis": "E08: M03 §3.2.1–3.2.4; details on dose, persistence and effect modification are self-designed / E10: M19 §19.1.2–19.2.4; self-developed application / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are self-designed / H08: M19 §19.1.2–19.2.4; self-developed application / H09: Chamgap's own interpretive boundary. References M19 principles; no formal causality tool was applied. The specific reason for applying this to this case is as follows: This is needed to avoid extending reporting gaps in a limited population/duration to safety in all populations or dosing recommendations. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link question-specific populations, exposure durations, interactions and safety-collection designs to review applicability." }, { "item_id": "N39", "question_type": "Limits on source-material access", "question": "Have the author copy/partial supplement and unread figures been distinguished?", "needed": "S01 publisher PDF, author HTML, supplements/figures, original tables and access history/versions", "role": "Required", "role_reason": "This is needed to avoid elevating reading tables in an author copy to visual verification of all original PDFs/supplements/figures.", "application_exception": "Do not import numerical interpretations of unread figures or unrelated recommended articles.", "criterion": "Preserve the historical HTML reading of Tables 1–3 and the unverified partial supplement, Figure 1/embedded graphs.", "basis": "C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E03: M08 Table 8.2.a, M03 §3.2.4; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid elevating reading tables in an author copy to visual verification of all original PDFs/supplements/figures. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare actual acquisition and reading locations by file/version and text/table/figure to review access scope." }, { "item_id": "N40", "question_type": "Corrections and versions", "question": "Were pre-submission manuscript corrections presented as new publisher corrections?", "needed": "Pre-submission corrections on 2026-09-16, original corrections.json, publication/retraction checks and event history", "role": "Supplementary", "role_reason": "This is needed to separate self-made manuscript corrections from official journal corrections/retractions and revisions to the verdict in this review.", "application_exception": "The historical separate corrections.json and ZIP were not read in this review; the existence/absence of official corrections is not newly established.", "criterion": "Record, by event, the historical correction/preservation of mixed treatment status, site, SD/SEM, denominators and conflicts/linkages.", "basis": "C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to separate self-made manuscript corrections from official journal corrections/retractions and revisions to the verdict in this review. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare source text before/after correction, reasons, events/versions and the scope of publication-status verification." }, { "item_id": "N41", "question_type": "Preservation of the original verdict", "question": "Were C/46 and self-verification reused as a new judgment on criteria?", "needed": "Original grade/score/safety, grade rationale, scope of self-verification/document quality and current criterion status", "role": "Supplementary", "role_reason": "This is needed to avoid turning historical scores or document quality A into a criterion-fulfillment rate, clinical certification or a new efficacy conclusion.", "application_exception": "Leave the original C/46, Caution, axes and historical calculations unchanged, as records separate from the table's criteria.", "criterion": "Preserve the original verdict and self-review scope without creating a new score, regrading or independent certification.", "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / E05: M15 §15.3.1–15.3.3; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid turning historical scores or document quality A into a criterion-fulfillment rate, clinical certification or a new efficacy conclusion. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Separate original verdict/quality metadata from the basis for new criterion statuses to review their linkage and display." }, { "item_id": "N42", "question_type": "Identity and publication history", "question": "Have the historical unassigned identity and current URL been kept from being read as contemporaneous?", "needed": "Lock timing, current assigned ID/URL, publication/deployment history and source-array identity", "role": "Supplementary", "role_reason": "This is needed to avoid confusing initial lock metadata with subsequent assignment/publication and the current unpublished table.", "application_exception": "Preserve both the historical linked-source list of 13 and the actual 20 sources/citations, without correcting original fields.", "criterion": "Distinguish, by event, the initial needs_id_assignment, current assigned/URL/prior deployment and nondeployment of the new table.", "basis": "C01: Question-clarification principles in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are self-designed / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is a self-developed application / C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules. The specific reason for applying this to this case is as follows: This is needed to avoid confusing initial lock metadata with subsequent assignment/publication and the current unpublished table. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Link original fields for identity/assignment/publication events to separate receipts to review timing differences." }, { "item_id": "N43", "question_type": "Cutoff date and search scope", "question": "Within what verification scope are replication/data described as unverified?", "needed": "Original 2026-09-16 search queries/results, scope of registry/publication/correction checks and the current review date", "role": "Required", "role_reason": "This is needed to avoid retrospectively recasting historical web searches and failures as a current exhaustive search or proof of research absence.", "application_exception": "Historical search logs were not read in this review, and no new searches/API queries or author contact are performed.", "criterion": "Separate the original evidence cutoff and records of 53 web searches/3 native-search failures from the date of this stored-summary conversion.", "basis": "C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is self-designed / E06: M08 Table 8.2.a, M04 §4.6.3; self-developed application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; self-developed application. The specific reason for applying this to this case is as follows: This is needed to avoid retrospectively recasting historical web searches and failures as a current exhaustive search or proof of research absence. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "In an authorized follow-up update, compare search sources, queries, timing, versions/results and the scope of absence statements." }, { "item_id": "N44", "question_type": "Current reading", "question": "Are summary reading and historical full-text access separated?", "needed": "Current input bytes, exact pointer/literal, current/historical access by material type and methods copies/SHA", "role": "Required", "role_reason": "This is needed to avoid presenting historical HTML/PDF/abstract access, partial visual checks or access failures as full-text reading in this review.", "application_exception": "Do not elevate actual methods HTML copies and references to historical ZIPs/separate calculations to new clinical/methods full-text reading.", "criterion": "Separate actual reading of the currently stored manuscript from historical_access_level, and leave all external material types unread in this review.", "basis": "C03: Data collection/selection principles in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are self-designed / C09: M04 §4.5, §4.6.3; limits on the current data conversion reflect the user-defined scope and self-designed rules. The specific reason for applying this to this case is as follows: This is needed to avoid presenting historical HTML/PDF/abstract access, partial visual checks or access failures as full-text reading in this review. This does not constitute a new full-text methods reading, formal application of RoB 2/GRADE/causality assessment, or certification of minimum clinical criteria.", "condition_origin": "Self-developed criteria individually written after reading the currently retained 3123 content; this is a known development case, not blinded or preregistered.", "proposed_research": "Compare input bytes, source-text locations, methods copies and actual actions by material type to verify the scope of reading badges." } ] }