{ "schema_version": "chamgap-public-criteria-1.0", "title": "Vitamin C (L-ascorbic acid) × Isotope-measured fractional iron absorption in nonanemic women with low iron stores", "criteria_version": "NGM-v3115-LOW-STORES-NONANEMIC-FIA-1.0", "criteria_date": "2026-10-05", "condition_origin": "Chamgap application criteria", "method_sources": [ { "id": "M03", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03", "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13", "official_principle": "Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.", "review_level": "Historical reuse of the 5 actual methods HTML copies/SHAs for 1585 and the principles recorded at that time. This is not new reading of full methods texts 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 the 5 actual methods HTML copies/SHAs for 1585 and the principles recorded at that time. This is not new reading of full methods texts 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 the 5 actual methods HTML copies/SHAs for 1585 and the principles recorded at that time. This is not new reading of full methods texts 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 the 5 actual methods HTML copies/SHAs for 1585 and the principles recorded at that time. This is not new reading of full methods texts 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 the 5 actual methods HTML copies/SHAs for 1585 and the principles recorded at that time. This is not new reading of full methods texts or formal application/certification." } ], "status_dictionary": { "Met": "Fulfillment of narrow documentation criteria, such as question/attribution, historical calculations, current versus past reading and versions. This is not clinical efficacy/safety certification or current verification of external full texts.", "Partly verified": "Actual retained reports exist, but verification of the relevant material remains outstanding, including original methods/plans, denominators/intervals and identity/access checks.", "Unverified": "Necessary materials/values cannot be established within the current input and the scope of verification at that time. This does not mean absence of new studies or an effect of 0.", "Not reported": "Limited to a record of nonreporting in a specific material/section actually read or in an explicitly identified historical summary. It is not extended to the entirety of external full texts not read this time.", "Conflicting information": "Incompatible records of the same fact retained in the current input. Here, these concern historical conflicts involving registration numbers and QA04, not a new cross-check or resolution against original texts.", "Inaccessible": "Used only when external access has actually failed this time. Because access is not attempted in this work, historical 403/failure records are not inherited as current status.", "Review incomplete": "Limited to review that actually remains outstanding or external materials not cross-checked this time. It does not mark all review of the retained stored summary as incomplete when that review has already been completed.", "Not applicable": "Confirmation for other populations, long-term use, clinical outcomes or individual safety does not apply to this table's narrow FIA question. This does not constitute absence of research, a null effect or safety certification for each extension." }, "requirements": [ { "item_id": "N01", "question_type": "Independent question", "question": "Which iron absorption comparison does this table address?", "needed": "Identity of the question: nonanemic women with low iron stores, oral single-ingredient L-ascorbic acid, an identical-iron comparator and isotope-measured fractional iron absorption", "role": "Required", "role_reason": "Needed to avoid merging this absorption question with anemia-treatment assessment 907, which involves the same ingredient and route, or with the energy classification.", "application_exception": "The subclaims array is empty. No additional main table is created for anemia treatment, Hb recovery, fatigue or long-term health effects.", "criterion": "Preserve the exact /ko/effect and link the scope to the single comparison adding 80 mg to the same fasted iron exposure.", "basis": "C01: Principles for clarifying the question in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / E09: M03 §3.2.4; internally defined limits on extrapolation. The rationale for application to this case is to avoid merging this absorption question with anemia-treatment assessment 907, which involves the same ingredient and route, or with the energy classification. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the original claim, population, exposure, comparator and endpoint to document included/excluded questions and the different Hb endpoint in 907." }, { "item_id": "N02", "question_type": "Main trial identity", "question": "To which article is the main absorption result attributed?", "needed": "Link between the stored summary and the title, DOI, PMID and Methods/Results locations of the von Siebenthal 2023 article", "role": "Required", "role_reason": "Needed to avoid interpreting ‘iron deficient’ in the bibliographic title as anemia-treatment evidence extending beyond the current population with Hb >12 g/dL.", "application_exception": "Verification of bibliographic agreement does not replace rereading the full text or certification of original-data accuracy.", "criterion": "Link the DOI 10.1002/ajh.26987, PMID 37357807 and main-result locations in S01 and S02 to the same article.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / C03: Principles for data collection/selection in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed. The rationale for application to this case is to avoid interpreting ‘iron deficient’ in the bibliographic title as anemia-treatment evidence extending beyond the current population with Hb >12 g/dL. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the article identity and citation locations, keeping the roles of other outcomes/cited reports separate." }, { "item_id": "N03", "question_type": "Report family", "question": "Are the 22 bibliographic entries being kept distinct from independent absorption trials?", "needed": "The same-article relationship of S01/S02/S03, the provisional registration link in S17 and the roles of each related article, official explanatory source, registration and 907", "role": "Required", "role_reason": "Needed to prevent an article's main text, index and appendix, safety explanations and registration clues from being double-counted as separate direct replications.", "application_exception": "Because sources and trial_families are absent from the current stored summary, no new definitive count of unique families for other cohorts is made.", "criterion": "Identify verified reports belonging to the same family and provisional/unverified links, distinguishing the bibliographic count from the number of direct trials.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / H07: M04 §4.6.1–4.6.2; adaptation for harms material is internally designed. The rationale for application to this case is to prevent an article's main text, index and appendix, safety explanations and registration clues from being double-counted as separate direct replications. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the DOI, registration, population/schedule and included-trial tables across all reports to audit family duplication and unverified relationships." }, { "item_id": "N04", "question_type": "Reading scope", "question": "Have materials actually read now been distinguished from full texts read in the past?", "needed": "Sections, bibliography and dates actually read in the current source's stored summary; historical HTML/index/mirror/failure records; and current status by external material type", "role": "Required", "role_reason": "Needed to avoid treating past verification or the existence of an original-source URL as external full-text reading performed this time.", "application_exception": "Preserve the past supplementary-material 403 and failed registration-history access as historical records, without labeling them as current inaccessibility.", "criterion": "Separate reading of the current stored summary from external access not attempted/materials not acquired/not read, and attach only links appropriate to each material type.", "basis": "C03: Principles for data collection/selection in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design. The rationale for application to this case is to avoid treating past verification or the existence of an original-source URL as external full-text reading performed this time. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Audit the current input scope and the access/acquisition/reading history by material type, and update separately only when an actual new reading event occurs." }, { "item_id": "N05", "question_type": "Selected population", "question": "What were the actual population's iron stores, anemia status and selection criteria?", "needed": "Criteria for the women's age, pregnancy/lactation, ferritin, Hb, CRP, BMI, weight and disease status, together with baseline characteristics/selection flow", "role": "Required", "role_reason": "Needed to avoid equating low iron stores with confirmed anemia or with all iron-deficient populations.", "application_exception": "Iron-store criteria alone do not establish vitamin C deficiency, absence of iron overload or representativeness.", "criterion": "Link ferritin ≤30 μg/L, Hb >12 g/dL and the other criteria for the actual nonpregnant, nonlactating women aged 18–45 years to the limits of applicability.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / E01: M08 §8.1–8.2.3; internal application. The rationale for application to this case is to avoid equating low iron stores with confirmed anemia or with all iron-deficient populations. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check inclusion/exclusion criteria, the baseline-characteristics table and recruitment flow to examine the actual analyzed population and scope of generalization." }, { "item_id": "N06", "question_type": "Baseline nutritional status", "question": "Can this be interpreted as an effect of correcting vitamin C deficiency or of the habitual diet?", "needed": "Baseline vitamin C testing, habitual diet/total intake and whether deficiency was a selection criterion", "role": "Required", "role_reason": "Needed to avoid recasting the absorption comparison as an effect of correcting vitamin C deficiency or of changing total dietary intake.", "application_exception": "Tests retained as not reported are not filled in as normal values or deficiency.", "criterion": "Identify the actual reporting scope for baseline vitamin C status, habitual diet and total intake, without classifying this as a deficiency trial.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. The rationale for application to this case is to avoid recasting the absorption comparison as an effect of correcting vitamin C deficiency or of changing total dietary intake. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check baseline nutritional testing, dietary records and intake by condition to distinguish deficiency status from the contribution of the added dose." }, { "item_id": "N07", "question_type": "Baseline risk screening", "question": "Have selection boundaries relating to iron, renal status and G6PD been verified?", "needed": "Entry criteria for TSAT and renal function, procedures for iron-overload and G6PD screening, and participant-specific records", "role": "Required", "role_reason": "Needed to avoid establishing specific screening or individual safety solely from a statement excluding major chronic diseases.", "application_exception": "The safety context of G6PD and high-dose intravenous administration is not transferred to the 80 mg oral exposure as an equivalent risk estimate.", "criterion": "Retain unverified information for each entry/screening record and identify boundaries for safety interpretation appropriate to the route and dose.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are internally designed / H08: M19 §19.1.2–19.2.4; internal application. The rationale for application to this case is to avoid establishing specific screening or individual safety solely from a statement excluding major chronic diseases. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check entry-test tables and exclusion/safety-screening records to examine the actual eligible population and separate vulnerable groups." }, { "item_id": "N08", "question_type": "Active ingredient identity", "question": "What are the identities of the trial's vitamin C ingredient and product?", "needed": "Actual manufacturing origin, lot and purity of Sigma Aldrich food-grade, single-ingredient L-ascorbic acid, and its distinction from other formulations", "role": "Required", "role_reason": "Needed to avoid assuming an exposure equivalent to salts, juice or combination products solely from a trade name or the name vitamin C.", "application_exception": "Do not fill unverified manufacturing origin, lot or purity with estimates, or infer product supply/funding from a brand name.", "criterion": "Distinguish food-grade L-ascorbic acid as a single ingredient from verified/unverified product attributes.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. The rationale for application to this case is to avoid assuming an exposure equivalent to salts, juice or combination products solely from a trade name or the name vitamin C. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check product specifications, trial batches and ingredient records to verify a reproducible identity for the active ingredient and formulation." }, { "item_id": "N09", "question_type": "Route of administration", "question": "By what route and in what prepared form were they administered together?", "needed": "Oral coadministration of L-ascorbic acid dissolved in water, distinguished from the iron capsule and meal/juice/intravenous conditions", "role": "Required", "role_reason": "Needed to avoid replacing the actual route and medium of the absorption comparison with efficacy or safety information from another route.", "application_exception": "An intravenous-administration trial is not required as direct evidence for this narrow oral condition.", "criterion": "Identify the addition of a single-ingredient oral aqueous solution together with exposure to the same iron capsule, excluding other routes/formulations.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / E08: M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed. The rationale for application to this case is to avoid replacing the actual route and medium of the absorption comparison with efficacy or safety information from another route. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check preparation/administration procedures, and design separate questions and direct comparisons when examining other routes/media." }, { "item_id": "N10", "question_type": "Iron exposure amount", "question": "How are the 100 mg capsule and the amount of isotope label distinguished?", "needed": "The capsule's 100 mg of elemental iron, the reported 3 mg label, the authors' molar ratio of 0.24:1 and explicit information on actual total elemental iron", "role": "Required", "role_reason": "Needed to avoid treating the capsule amount as total exposure or arbitrarily deriving absolute absorbed mg from fractional absorption.", "application_exception": "Do not add the reported label amount to create a new total or recalculate the authors' molar ratio.", "criterion": "Preserve separately the nominal capsule amount, label amount, unverified total and author-reported molar ratio.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. The rationale for application to this case is to avoid treating the capsule amount as total exposure or arbitrarily deriving absolute absorbed mg from fractional absorption. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check preparation/label masses and the actual total-dose table to distinguish the different estimands for fractional and absolute amounts." }, { "item_id": "N11", "question_type": "Actual comparator", "question": "Apart from the added 80 mg, are the iron and water exposures identical in the main comparison?", "needed": "The same participant's exposure to the same labeled iron capsule and 200 mL of water, with or without added ascorbic acid, and actual records of common concomitant treatments", "role": "Required", "role_reason": "Needed to distinguish the contribution of added vitamin C from other differences in iron dose, medium or concomitant treatments.", "application_exception": "Compare only the two selected conditions, without forcing all elements of the 6 different conditions into a common control.", "criterion": "Link the selected main comparison to whether it adds only 80 mg of ascorbic acid under the same fasted iron-and-water conditions.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. The rationale for application to this case is to distinguish the contribution of added vitamin C from other differences in iron dose, medium or concomitant treatments. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the composition/common-treatment table for each dosing condition to audit the actual comparison of interest and differences in concomitant treatments/media." }, { "item_id": "N12", "question_type": "Fasting and timing", "question": "What were the meal and morning dosing conditions for the absorption comparison?", "needed": "Procedures for overnight fasting, morning dosing at 07:00–09:00 and simultaneous administration, with actual adherence records by condition", "role": "Required", "role_reason": "Needed to avoid extending the result for high-dose iron in the fasted state to an identical effect size during routine use with meals.", "application_exception": "Do not arbitrarily attribute the 1 withdrawal due to difficulty adhering to fasting to a safety event or failure of a particular condition.", "criterion": "Identify fasting, administration time, simultaneous administration and unverified adherence separately.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / E08: M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed. The rationale for application to this case is to avoid extending the result for high-dose iron in the fasted state to an identical effect size during routine use with meals. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check meal/administration diaries and observation records, and examine questions about dosing after meals or at different times through separate comparisons." }, { "item_id": "N13", "question_type": "Exposure and blood-sampling schedule", "question": "Have single-exposure absorption measurements been distinguished from the duration of long-term use?", "needed": "Dosing days 1·3·5·22·24·26 for the 6 conditions, blood sampling on days 22/43 in the Methods section, incorporation measurements 17–21 days after administration of each label and records of conflicting information", "role": "Required", "role_reason": "Needed to avoid turning the incorporation-observation period into a period of long-term vitamin C administration or sustained absorption effects.", "application_exception": "Preserve the Methods schedule with its source attribution, without treating it as a definitive resolution of the conflicting final blood-sampling dates.", "criterion": "Separate exposure 1 time per condition from the incorporation-measurement window, linking both the Methods schedule and the unresolved schedule conflict.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / E08: M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed. The rationale for application to this case is to avoid turning the incorporation-observation period into a period of long-term vitamin C administration or sustained absorption effects. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check dosing/blood-sampling schedules, figures and registration history by date to verify the exposure window and label-specific observation windows." }, { "item_id": "N14", "question_type": "Allocation and blinding", "question": "What was the actual extent of crossover allocation and blinding?", "needed": "Computer-generated crossover sequence, allocation-concealment/laboratory-blinding/open-label procedures, and baseline/sequence data", "role": "Required", "role_reason": "Needed to avoid assuming that concealment, assessment blinding or allocation problems have been resolved solely because the study is described as randomized.", "application_exception": "An open-label design or unreported blinding does not automatically render the measurement invalid.", "criterion": "Distinguish the actual open-label randomized crossover design and reported/unreported procedures in relation to the endpoint.", "basis": "E01: M08 §8.1–8.2.3; internal application / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C04: M03 §3.2.1; detailed population criteria are internally designed. The rationale for application to this case is to avoid assuming that concealment, assessment blinding or allocation problems have been resolved solely because the study is described as randomized. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check random-sequence generation, allocation/testing procedures and baseline data by sequence to examine allocation limitations for the selected result." }, { "item_id": "N15", "question_type": "Participant and observation denominators", "question": "Can 35 participants, 34 participants and 204 observations be distinguished?", "needed": "35 enrolled participants, 34 analyzed participants who completed the 6 conditions, 204 observations, and linkage of the same participants across the two selected conditions", "role": "Required", "role_reason": "Needed to avoid counting repeated observations as people or combining the same 34 participants as two independent groups.", "application_exception": "Do not turn 204 observations into 204 participants or calculate a new total participant count.", "criterion": "Link the original enrollment/completion/analysis/observation counts unchanged, identifying the comparison as paired within the same 34 participants.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. The rationale for application to this case is to avoid counting repeated observations as people or combining the same 34 participants as two independent groups. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check participant flow and condition-specific analysis tables to distinguish denominators for people, repeated observations and pairs." }, { "item_id": "N16", "question_type": "Analysis and attrition", "question": "Have the completer analysis, withdrawal and imputation records been distinguished?", "needed": "Reason/condition for the 1 withdrawal after the first visit, the per-protocol completer analysis, and separate handling of CRP imputation and missing FIA data", "role": "Required", "role_reason": "Needed to avoid treating completer results as the effect in all randomized participants or mistaking CRP imputation for absorption-rate imputation.", "application_exception": "Do not attribute the withdrawal to an adverse effect of iron or vitamin C while its condition remains unverified.", "criterion": "Preserve separately the distinction between the analysis of 34 completers and enrollment of 35 participants, the imputed variable and the unverified condition of withdrawal.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application. The rationale for application to this case is to avoid treating completer results as the effect in all randomized participants or mistaking CRP imputation for absorption-rate imputation. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the flow diagram, missing-data/imputation rules and analysis code to examine the distinction between effects of assignment and adherence, and the possible influence of attrition." }, { "item_id": "N17", "question_type": "Handling of the crossover design", "question": "How were adherence and period, sequence and carryover effects handled?", "needed": "Records of supervised administration, period/sequence/carryover effects and interactions, and definitions of the actual crossover model and contrast", "role": "Required", "role_reason": "Needed to avoid assuming that time/sequence effects and all confounding were eliminated solely because the comparison was repeated within the same individuals.", "application_exception": "Unverified interactions are not treated as established carryover bias or a null effect.", "criterion": "Separate the reporting level for supervised administration from unverified crossover handling, and link the scope of verification for paired/adjusted effects.", "basis": "E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / E04: M08 §8.2.2, M15 §15.3.1; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed. The rationale for application to this case is to avoid assuming that time/sequence effects and all confounding were eliminated solely because the comparison was repeated within the same individuals. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check administration logs, the repeated-measures model, period/sequence terms and prespecified contrasts to examine the adequacy of the crossover handling." }, { "item_id": "N18", "question_type": "Isotope measurement", "question": "Which test and unit define the fractional iron absorption result?", "needed": "Erythrocyte incorporation of 54Fe·57Fe·58Fe, the dilution method, label-specific measurement windows, the definition of FIA (%) and assay quality", "role": "Required", "role_reason": "Needed to avoid confusing increased blood iron, Hb recovery or ferritin changes with actual stable-isotope absorption measurements.", "application_exception": "An objective test is not converted into direct proof of clinical events/patient-centered benefit.", "criterion": "Link the selected endpoint to stable-isotope-derived FIA (%) and distinguish it from other iron/hemoglobin outcomes.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / E09: M03 §3.2.4; internally defined limits on extrapolation. The rationale for application to this case is to avoid confusing increased blood iron, Hb recovery or ferritin changes with actual stable-isotope absorption measurements. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check isotope assays, label-specific incorporation/dilution procedures and outcome units to examine measurement limitations of the selected endpoint." }, { "item_id": "N19", "question_type": "Incorporation model", "question": "What does the assumption of 80% erythrocyte incorporation mean?", "needed": "The 80% incorporation assumption used in the absorption calculation, individual incorporation fractions and the relevant location in the IAEA method", "role": "Required", "role_reason": "Needed to avoid turning a model assumption into an identical incorporation rate actually measured in every participant.", "application_exception": "The IAEA methods explanation is neither an individual measurement in participants in 3115 nor a new replication trial.", "criterion": "Identify the 80% assumption and the unverified individual fractions, distinguishing methodological explanation from clinical outcome data.", "basis": "E03: M08 Table 8.2.a, M03 §3.2.4; internal application / E04: M08 §8.2.2, M15 §15.3.1; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed. The rationale for application to this case is to avoid turning a model assumption into an identical incorporation rate actually measured in every participant. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the absorption model/assumptions against individual incorporation data, and examine interpretation of changes to assumptions through an appropriate prespecified analysis." }, { "item_id": "N20", "question_type": "Prespecified endpoints and multiple comparisons", "question": "Have the prespecified hierarchy and analysis plan for the selected absorption comparison been verified?", "needed": "Prespecified primary/secondary comparisons among the 6 conditions, protocol, SAP, registration history, handling of multiple comparisons and records of actual outcome changes", "role": "Required", "role_reason": "Needed to avoid promoting the page's selected main comparison to the trial's prospective primary endpoint or to evidence of no selective reporting.", "application_exception": "Failure to acquire a plan is not converted into proof of nonregistration or outcome switching.", "criterion": "Separate the current page's comparison from the unverified prospective trial hierarchy, and retain the record of no adjustment for multiple comparisons.", "basis": "E06: M08 Table 8.2.a, M04 §4.6.3; internal application / C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed. The rationale for application to this case is to avoid promoting the page's selected main comparison to the trial's prospective primary endpoint or to evidence of no selective reporting. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check initial/revised registrations, the protocol, SAP and actual results for the 6 conditions to verify the endpoint/contrast hierarchy and reasons for changes." }, { "item_id": "N21", "question_type": "Main absorption observation", "question": "What are the actual medians, IQRs and P for the two conditions?", "needed": "FIA medians, IQRs and P with/without the added 80 mg in the same 34 participants, with the corresponding table/figure and test contrast", "role": "Required", "role_reason": "Needed to preserve the positive absorption observation while keeping the different statistics represented by medians, IQRs and P distinct.", "application_exception": "An IQR is not a confidence interval, and a significant P is not sufficient evidence of clinical importance or precision.", "criterion": "Attribute the added condition's 26.7% (IQR 19.1–32.6%) and the no-addition condition's 20.6% (IQR 12.3–25.5%), the same 34 participants and P<0.001 to their original location.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / E05: M15 §15.3.1–15.3.3; internal application. The rationale for application to this case is to preserve the positive absorption observation while keeping the different statistics represented by medians, IQRs and P distinct. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the original table/figure and test contrast to verify agreement of the reported medians, distributions, P and analysis denominator." }, { "item_id": "N22", "question_type": "Historical descriptive arithmetic", "question": "As which estimand are 6.1%p, 1.296 and 29.6% preserved?", "needed": "Historical arithmetic records of differences/ratios of marginal medians, distinguished from individual changes and adjusted crossover effects", "role": "Required", "role_reason": "Needed to avoid turning descriptive arithmetic on reported medians into an average individual effect or a model-adjusted estimate.", "application_exception": "Do not perform new arithmetic or reconstruct paired/standardized effects from IQR/P.", "criterion": "Preserve the historical 6.1%p, 1.296 and approximately 29.6% only as descriptive comparisons of marginal medians.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / E05: M15 §15.3.1–15.3.3; internal application. The rationale for application to this case is to avoid turning descriptive arithmetic on reported medians into an average individual effect or a model-adjusted estimate. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check inputs, units and estimands in the retained calculation record against the original results to distinguish descriptive arithmetic from inferential estimation." }, { "item_id": "N23", "question_type": "Variance and intervals", "question": "Can the CI, SD and SE for the exact paired effect be verified?", "needed": "The paired/model-adjusted effect, CI, SD, SE, exact test statistic and analysis definition for the selected contrast", "role": "Required", "role_reason": "Needed to avoid filling in the current paired precision using a P-value bound and IQR, or an SD used for sample-size planning in another study.", "application_exception": "Absent or unverified variances/intervals are not calculated and inserted, nor interpreted as absence of an absorption direction.", "criterion": "Retain the empty interval/variance values and reasons for nonverification for the current contrast, without substituting variance from another study.", "basis": "E04: M08 §8.2.2, M15 §15.3.1; internal application / E05: M15 §15.3.1–15.3.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations by design are internally designed. The rationale for application to this case is to avoid filling in the current paired precision using a P-value bound and IQR, or an SD used for sample-size planning in another study. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Acquire the analysis output, paired data and model SE/CI for the selected contrast, and cross-check them against the original estimand/denominator." }, { "item_id": "N24", "question_type": "Importance and clinical benefit", "question": "Has the clinical meaning of the FIA difference been verified?", "needed": "A justified importance threshold for absorption itself, together with separate Hb/anemia/patient-centered outcomes and follow-up data", "role": "Supplementary; required for extension to clinical benefit", "role_reason": "Needed to avoid automatically extending the direction of a short-term physiological surrogate to anemia treatment or improvement in fatigue/health.", "application_exception": "Do not require an anemia-event trial for the narrow absorption question or invent a common numerical MCID.", "criterion": "Distinguish the absorption observation from unverified clinical importance, and retain Hb/health questions as separate endpoints.", "basis": "E05: M15 §15.3.1–15.3.3; internal application / E09: M03 §3.2.4; internally defined limits on extrapolation / C01: Principles for clarifying the question in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed. The rationale for application to this case is to avoid automatically extending the direction of a short-term physiological surrogate to anemia treatment or improvement in fatigue/health. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Examine the basis for absorption's importance and direct clinical outcomes by endpoint, designing a separate long-term clinical comparison if needed." }, { "item_id": "N25", "question_type": "Registration identity", "question": "How have the article's registration number and the probably matching mirror been distinguished?", "needed": "The printed NCT04074707 and identity of the pregnancy registration, the similar conditions/investigators/enrollment in the NCT05414474 mirror, and official version history", "role": "Required", "role_reason": "Needed to avoid retaining an incorrectly linked number as correct or promoting an inference from a mirror to confirmation of official prospective registration.", "application_exception": "Do not label failure to acquire the official history as absence of registration, or invent a link when the mirror's actual URL is unavailable.", "criterion": "Identify the mismatch in the printed number and the provisional link to NCT05414474 separately, retaining the official history as unverified.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed / C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design / E06: M08 Table 8.2.a, M04 §4.6.3; internal application. The rationale for application to this case is to avoid retaining an incorrectly linked number as correct or promoting an inference from a mirror to confirmation of official prospective registration. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the official initial/revised registration history against the population, 6 conditions, investigators and enrollment in the article/mirror to verify the actual link." }, { "item_id": "N26", "question_type": "Preservation of discrepancies", "question": "Have conflicts involving recruitment, blood sampling, registration criteria and secondary results been preserved?", "needed": "Pairs of original records for recruitment year, final blood-sampling day, registration criteria, coffee P and the reference median, with evidence of correction/resolution", "role": "Required", "role_reason": "Needed to avoid erasing historical discrepancies by choosing a statement from a single source or inventing a currently unavailable counterpart value.", "application_exception": "Do not treat every difference in values across conditions as a conflict. Do not add counterpart values for conflicts when they are absent from the current original stored summary.", "criterion": "Identify the retained types of conflict and their scope, leaving unverified any parts lacking both original values/locations.", "basis": "C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed / E06: M08 Table 8.2.a, M04 §4.6.3; internal application / C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design. The rationale for application to this case is to avoid erasing historical discrepancies by choosing a statement from a single source or inventing a currently unavailable counterpart value. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the article's Methods, figures/results, original registration versions and correction records fact by fact, preserving incompatible pairs and the evidence for resolution." }, { "item_id": "N27", "question_type": "Supplementary material", "question": "What is the actual acquisition scope for S1, S2 and the supplementary material?", "needed": "Corrected DOCX URL, original S1/S2 tables, content/version and actual access/acquisition records", "role": "Required", "role_reason": "Needed to avoid treating appendix references and link correction as verification of appendix content.", "application_exception": "The 403 on 2026-09-16 is a historical failure. External access not attempted this time is not marked as current inaccessibility.", "criterion": "Preserve the actual download URL, past failure and unverified S1/S2, keeping the current material type marked as not read.", "basis": "C03: Principles for data collection/selection in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application / E06: M08 Table 8.2.a, M04 §4.6.3; internal application. The rationale for application to this case is to avoid treating appendix references and link correction as verification of appendix content. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Upon an authorized actual acquisition event, cross-check the DOCX version/original bytes and S1/S2 against the main-text contrasts, denominators and variances." }, { "item_id": "N28", "question_type": "Additional dose and juice", "question": "Can the findings be extended to the 500 mg comparison or juice alone?", "needed": "Actual contrasts, variances/intervals for 500 mg versus 80 mg/water, and whether orange juice alone was measured separately", "role": "Supplementary; required for extension to dose/juice claims", "role_reason": "Needed to avoid turning an unverified additional increase into equivalence/an optimal dose or inventing an unmeasured juice effect.", "application_exception": "Do not require trials of every dose for the narrow 80 mg main comparison.", "criterion": "Attribute P=0.226 for 500 mg to its corresponding contrast, without interpreting it as equivalence, an optimal dose or an effect of juice alone.", "basis": "E08: M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed / E05: M15 §15.3.1–15.3.3; internal application. The rationale for application to this case is to avoid turning an unverified additional increase into equivalence/an optimal dose or inventing an unmeasured juice effect. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Examine prespecified dose contrasts/intervals, and address equivalence, optimal-dose or juice-alone questions through appropriate separate direct comparisons." }, { "item_id": "N29", "question_type": "Other comparisons among the 6 conditions", "question": "Have secondary comparisons involving meals, coffee, timing and similar factors been kept separate from the main comparison?", "needed": "Actual compositions, times and endpoint contrasts for the same trial's 6 conditions, and original records of conflicts in coffee P/reference medians", "role": "Required", "role_reason": "Needed to avoid merging every contrast in the same trial into an identical effect or independent replication of adding AA 80 mg in the fasted state.", "application_exception": "The current input only references other_conditions.json; it was not opened. No secondary-condition numbers or counterpart values for conflicts are filled in.", "criterion": "Separate the two selected conditions from other contrasts, leaving unavailable secondary results within the bibliographic/reference scope.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. The rationale for application to this case is to avoid merging every contrast in the same trial into an identical effect or independent replication of adding AA 80 mg in the fasted state. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Check the table of 6 conditions, prespecified contrasts and original other_conditions records to attribute each result individually to the corresponding composition/time." }, { "item_id": "N30", "question_type": "Related dietary studies", "question": "What roles do the long-term balance, dietary and nonsimultaneous-administration studies in S05–S08 play?", "needed": "Each study's actual population, diet/simultaneous exposure, absorption/balance endpoint, timing and original results/denominators", "role": "Required", "role_reason": "Needed to avoid merging null findings from other dietary/long-term balance studies into direct refutation of the main comparison, or counting them as direct replications from titles alone.", "application_exception": "Do not reconstruct unprovided numbers, effects or durations from bibliographic entries that only reference sources.json.", "criterion": "Retain S05–S08 as related material, while explaining how their conditions/measures differ from the same fasted-capsule comparison with simultaneous 80 mg administration.", "basis": "E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed. The rationale for application to this case is to avoid merging null findings from other dietary/long-term balance studies into direct refutation of the main comparison, or counting them as direct replications from titles alone. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check each article's methods/original results separately to verify differences in simultaneous exposure, dietary changes, balance and isotope endpoints." }, { "item_id": "N31", "question_type": "Other populations and iron formulations", "question": "Can S09–S12 and S21 be combined as effects for the same main comparison?", "needed": "Actual ingredients/populations/measures and results in studies of overweight/obesity or inflammation, food fortification/phytase/Na2EDTA, and iron dosing schedules", "role": "Required", "role_reason": "Needed to avoid turning results from other populations, combined compositions, iron schedules or hematological outcomes into direct absorption replications of single-ingredient AA addition.", "application_exception": "Do not claim verification of a full text or direct result solely from S11's title and methods citation or S12's publication timing.", "criterion": "Identify each bibliographic entry's different population/intervention/endpoint, without automatically adding it to the count of directly eligible families.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptation for each question is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. The rationale for application to this case is to avoid turning results from other populations, combined compositions, iron schedules or hematological outcomes into direct absorption replications of single-ingredient AA addition. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Verify the actual populations, exposure/concomitant treatments, endpoints and study families of related studies individually to assess their directness for this question." }, { "item_id": "N32", "question_type": "Registration and review leads", "question": "Has discovery of registrations/reviews in S18–S20 been treated as verification of results?", "needed": "Actual result status in the INSECTE registration, the included-trial table in the fruit/juice review, and the exact FeHydroA registration URL and original results", "role": "Required", "role_reason": "Needed to avoid promoting registered plans, review discovery or unresolved search leads to independent positive/no-difference absorption trials.", "application_exception": "When an exact URL is unverified, do not attach a portal homepage as though it were the link to the specific original record.", "criterion": "Retain the level of plan/index/review discovery, distinguishing the absence of results, included-trial information or a confirmed URL.", "basis": "C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application / C03: Principles for data collection/selection in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design / E06: M08 Table 8.2.a, M04 §4.6.3; internal application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. The rationale for application to this case is to avoid promoting registered plans, review discovery or unresolved search leads to independent positive/no-difference absorption trials. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check posted registration results, review tables of included trials and exact records to distinguish unique trials/reports from information that remains a plan." }, { "item_id": "N33", "question_type": "Funding and product supply", "question": "What is the verification scope for ETH funding, product supply and conflicts of interest?", "needed": "Actual records of ETH Zurich Laboratory of Human Nutrition funding, declarations of competing financial interests, product supply and institutional/author relationships", "role": "Required", "role_reason": "Needed to avoid treating academic funding/a declaration of no competing interests as proof of complete independence or absence of bias, or inferring sponsorship from a brand name.", "application_exception": "The existing I2 axis is preserved as a historical value, without being used as a new independence grade or certification of replication across families.", "criterion": "Distinguish reported funding/declarations from unreported product supply, retaining relationships that remain unverified.", "basis": "C10: Chamgap's own independence/attribution criteria. The formal methods sections used in this pilot do not endorse every detail of this item / C02: Distinction between studies and reports in M04 §4.6.1–4.6.2; cohort/outcome linkage is an internal application. The rationale for application to this case is to avoid treating academic funding/a declaration of no competing interests as proof of complete independence or absence of bias, or inferring sponsorship from a brand name. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check funding/acknowledgments/COI and product-supply records to examine the level of disclosure and scope of funding/institutional independence." }, { "item_id": "N34", "question_type": "Collection of trial harms data", "question": "Can adverse reactions and withdrawal frequencies under the same conditions be verified?", "needed": "Condition-specific AE definitions, collection methods, numbers of exposed people/people with events, event counts and periods, and the condition/causal attribution of the fasting-related withdrawal", "role": "Supplementary; required for extension to comparative harms/safety", "role_reason": "Needed to avoid turning positive absorption findings or unreported condition-specific AEs into absence of adverse effects or proof of safety.", "application_exception": "Do not arbitrarily classify the 1 withdrawal due to difficulty maintaining the fast as vitamin C harm or as 0 events.", "criterion": "Separate the record of AEs not reported from the withdrawal reason/unverified condition, without newly calculating incidence or establishing causality.", "basis": "E10: M19 §19.1.2–19.2.4; internal application / H01: M19 §19.1.2–19.2.4; detailed distinctions are internally designed / H02: Design-specific harms questions in M19 §19.2; temporal-relationship details are internally designed / H03: M19 §19.2.2–19.2.4, M03 §3.2.3; internal application / H04: M19 §19.1.2–19.2.4; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / H09: Chamgap's own interpretive boundaries. These reference M19 principles and do not constitute formal application of a causality tool. The rationale for application to this case is to avoid turning positive absorption findings or unreported condition-specific AEs into absence of adverse effects or proof of safety. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Cross-check the AE collection plan, condition-specific event/exposure/withdrawal tables and follow-up records to verify event frequency and the scope of signal interpretation." }, { "item_id": "N35", "question_type": "Official safety background", "question": "Which safety questions do the NIH, NIDDK and NCI materials address?", "needed": "Scope of the UL of 2,000 mg/day for adults aged 19 years and older, caution concerning iron overload, the high-dose intravenous/G6PD context and the actual route/dose", "role": "Supplementary; required for extension to individual/vulnerable-group safety", "role_reason": "Needed to avoid promoting official general safety background to individual safety or event incidence in this 80 mg oral trial.", "application_exception": "The UL is neither an individual's recommended intake nor a guarantee of unrestricted safety, and the same adult threshold is not extended to age 18.", "criterion": "Separate the actual population, route/dose and general background role of each official source.", "basis": "E10: M19 §19.1.2–19.2.4; internal application / H05: Design considerations in M19 §19.2.2–19.2.4; detailed confounding records are internally designed / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. These reference M19 principles and do not constitute formal application of a causality tool / C04: M03 §3.2.1; detailed population criteria are internally designed / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptation for testing are internally designed. The rationale for application to this case is to avoid promoting official general safety background to individual safety or event incidence in this 80 mg oral trial. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Compare the populations/routes/doses in official safety materials with the trial, examining direct harms comparisons separately from general cautions." }, { "item_id": "N36", "question_type": "Extension of applicability", "question": "Can the same effect be applied to other populations, durations and health endpoints?", "needed": "Direct data for men, older people, normal iron stores, anemia, pregnancy/lactation, children, renal disease/inflammation/iron overload and long-term/health endpoints", "role": "Supplementary; required for extended claims", "role_reason": "Needed to avoid extending an acute surrogate in a limited population of young nonanemic women to health benefit or safety for everyone.", "application_exception": "Trials for each extension question are not required to complete the narrow main comparison, and these questions are not converted into a general absence of evidence or an effect of 0.", "criterion": "Distinguish the original population/single-exposure FIA from unverified direct evidence for excluded populations and long-term/clinical endpoints.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / E08: M03 §3.2.1–3.2.4; details of dose, duration and effect modification are internally designed / E09: M03 §3.2.4; internally defined limits on extrapolation / H08: M19 §19.1.2–19.2.4; internal application. The rationale for application to this case is to avoid extending an acute surrogate in a limited population of young nonanemic women to health benefit or safety for everyone. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Examine direct comparisons and prespecified subgroups/interactions separately by population, exposure, duration and endpoint, designing necessary extension questions separately." }, { "item_id": "N37", "question_type": "Preservation of the existing assessment", "question": "Have the original C/50, Caution and axes been kept from being reused as new criterion statuses?", "needed": "Separation of historical values for the original grade, score, safety, axes, document quality and assessment calculations from the new row statuses", "role": "Required", "role_reason": "Needed to avoid arbitrarily introducing n<200 or other existing scoring rules as new sufficiency criteria, or converting them into a criterion-fulfillment rate or clinical certification.", "application_exception": "The original grade and numbers are neither deleted nor regraded. document_quality A and efficacy C are different original fields.", "criterion": "Preserve the original assessment, axes and historical calculations unchanged, and let new criterion statuses represent only individual record/gap review.", "basis": "C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design / E05: M15 §15.3.1–15.3.3; internal application / H09: Chamgap's own interpretive boundaries. These reference M19 principles and do not constitute formal application of a causality tool. The rationale for application to this case is to avoid arbitrarily introducing n<200 or other existing scoring rules as new sufficiency criteria, or converting them into a criterion-fulfillment rate or clinical certification. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Compare hashes/values between the original input and the produced version to check preservation of the assessment, axes and calculations, and audit the meaning of criterion statuses separately." }, { "item_id": "N38", "question_type": "Reference dates and version records", "question": "Have this table's input, criterion freeze, application and verification scope been recorded?", "needed": "The 2026-09-16 evidence cutoff and search scope at that time; the actual 2026-10-05 review, original bytes/SHA, and records of criteria frozen before application", "role": "Required", "role_reason": "Needed to avoid overstating transformation of the stored summary as an up-to-date comprehensive search, clinical preregistration, methodological certification or completed deployment.", "application_exception": "These are internally developed criteria for a development case already read. The 59 searches and 1 failure are historical records, not new searches in this work.", "criterion": "Link criterion versions/hashes with actual freeze→record→application→writing times, explicitly stating the scope and absence of new work.", "basis": "C03: Principles for data collection/selection in M04 §4.5–4.6; separation of access from reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limits on the current data transformation follow the user-defined scope and internal design / C01: Principles for clarifying the question in M03 §3.1, §3.2.1–3.2.4; detailed separation rules are internally designed. The rationale for application to this case is to avoid overstating transformation of the stored summary as an up-to-date comprehensive search, clinical preregistration, methodological certification or completed deployment. This does not constitute new reading of full methods texts, formal application of RoB 2/GRADE/causal tools or certification of minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the current retained manuscript/evidence and bibliography for 3115 and the actual family definitions. This is a known development case, not a blinded exercise or clinical preregistration.", "proposed_research": "Audit original bytes, pointers, versions/event times and row-level model records, updating new-material/criterion-revision events separately." } ] }