{ "schema_version": "chamgap-public-criteria-1.0", "title": "Vitamin B12 (actual chemical form unverified) × Reduction of CIS subjective-fatigue score in adults with IBD-related fatigue", "criteria_version": "NGM-v3114-ORAL-B12-IBD-CIS8-1.0", "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": "Reuse of the actual bytes/SHA of the methods HTML copies retained for 1585 and of historical principles. This is not new full-text reading of methods, official implementation or certification in this run." }, { "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": "Reuse of the actual bytes/SHA of the methods HTML copies retained for 1585 and of historical principles. This is not new full-text reading of methods, official implementation or certification in this run." }, { "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": "Reuse of the actual bytes/SHA of the methods HTML copies retained for 1585 and of historical principles. This is not new full-text reading of methods, official implementation or certification in this run." }, { "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": "Reuse of the actual bytes/SHA of the methods HTML copies retained for 1585 and of historical principles. This is not new full-text reading of methods, official implementation or certification in this run." }, { "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": "Reuse of the actual bytes/SHA of the methods HTML copies retained for 1585 and of historical principles. This is not new full-text reading of methods, official implementation or certification in this run." } ], "status_dictionary": { "Met": "The criterion's identity, retained attribution and interpretive boundaries have been verified. This does not establish clinical efficacy, safety or official certification.", "Partly verified": "Some facts concerning the criterion are retained, but comparison of required axes/original materials remains outstanding.", "Unverified": "The required values/materials cannot be established within the retained content read. This does not mean 0 studies/effect/events.", "Does not apply": "An extension requirement that does not apply to the required conditions of the current narrow question. It does not mean the materials are verified or substitute for Not read.", "Not applicable": "An extension requirement that does not apply to the required conditions of the current narrow question.", "Not read": "The corresponding original material was not directly read in this run. This is distinguished from actual reading of the local stored summary.", "Not reported": "An information gap limited to the material/section read. This is not a conclusion that the information is absent throughout the original article.", "Inaccessible": "Used only when an actual current failure is recorded; current access not attempted and historical failures are distinguished.", "Conflicting information": "Marked only when an actual discrepancy is linked to the same question/analysis.", "Review incomplete": "Individual review for table production remains outstanding; this is distinguished from Unverified/Not read material statuses." }, "requirements": [ { "item_id": "N01", "question_type": "Independent claim", "question": "Has the question of CIS subjective fatigue in IBD been linked as a single unit?", "needed": "Link the original /ko/effect to oral B12 as the sole added therapy versus placebo in adults with IBD, with the reported between-group difference in CIS subjective-fatigue change at 8 weeks, and distinguish other populations and endpoints. Materials needed: the current claim, facets and identity manuscript, and the complete preceding version if the scope changes.", "role": "Required", "role_reason": "This identity criterion prevents the entire ingredient or all fatigue studies from being combined into a single effect.", "application_exception": "Preserve the empty subclaims list as the actual structure. Do not automatically create additional subclaims for the mixed cohort, anemia, vitality or motivation.", "criterion": "Link the original /ko/effect to oral B12 as the sole added therapy versus placebo in adults with IBD, with the reported between-group difference in CIS subjective-fatigue change at 8 weeks, and distinguish other populations and endpoints.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.4; internally defined boundaries on extension — an individual internal adaptation for the independent claim, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "When a new claim is requested, separate its population, route, comparator, endpoint and time point, and first review the relationship between the original ID and the question." }, { "item_id": "N02", "question_type": "Report family", "question": "Has the family relationship between the same reports and the provisional registration been confirmed?", "needed": "Group the S01·S02·S16 abstracts and S03 full-text link into the same report family, and do not count the S04 candidate registration or S05 review requotation as independent replication. Materials needed: article DOI/PMID, original registry record, review table of excluded studies and report linkage table.", "role": "Required", "role_reason": "This is needed to prevent 17 citations from being converted into 17 independent trials or a unique participant count.", "application_exception": "The S04 linkage is provisional. A candidate registration number alone does not confirm the same family or create new results.", "criterion": "Group the S01·S02·S16 abstracts and S03 full-text link into the same report family, and do not count the S04 candidate registration or S05 review requotation as independent replication.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual internal adaptation for the report family, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare authors, periods, populations and registration identities in the original reports to update the family table, retaining unconfirmed linkages as candidates." }, { "item_id": "N03", "question_type": "Actual reading", "question": "Has reading summaries in this run been distinguished from past access to abstracts and full texts?", "needed": "Link the locations in the source stored summaries read in this run, and separate each external material's current access not attempted, not acquired and not read states from its historical access_level. Materials needed: current input bytes, row-level pointers and records of reading/accessing each original material.", "role": "Required", "role_reason": "This is needed to prevent a current full-text-read badge from being displayed solely on the basis of a URL or a past reading record.", "application_exception": "Past failures for S03·S04·S12 are not failures of a current retry. The separate sealed audit in S17 was also not read in this run.", "criterion": "Link the locations in the source stored summaries read in this run, and separate each external material's current access not attempted, not acquired and not read states from its historical access_level.", "basis": "M04 §4.5–4.6 principles for collecting/selecting materials; separation of access and reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limitations on the current material conversion reflect user-defined scope and internal design — an individual internal adaptation for actual reading, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "For each subsequently permitted actual access event, separately record the material type, attempt result, sections read and date, and distinguish these from summary links." }, { "item_id": "N04", "question_type": "Search and correction scope", "question": "Has the absence of verified direct results been limited to the historical search scope?", "needed": "State the evidence cutoff date and the limits of the search and correction checks at that time, without implying that a new search was conducted in this run. Materials needed: original search/access records from that time, title/DOI-specific correction-check records and subsequent update events.", "role": "Required", "role_reason": "This is needed to prevent the lack of verified directly eligible results from being extended to worldwide absence of research or a complete current search.", "application_exception": "An empty corrections field means only that the retained list is empty; it does not prove the absence of all corrections and retractions.", "criterion": "State the evidence cutoff date and the limits of the search and correction checks at that time, without implying that a new search was conducted in this run.", "basis": "M04 §4.5, §4.6.3; limitations on the current material conversion reflect user-defined scope and internal design; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — an individual internal adaptation for search and correction scope, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "When a new search is authorized, record search strategies, dates, registry/unpublished/correction routes and failures, and compare the existing results as well." }, { "item_id": "N05", "question_type": "Directness for the IBD stratum", "question": "Have separate fatigue results and arm-specific analysis denominators for the IBD stratum been verified?", "needed": "Actual separate results and analysis denominators for the IBD stratum are required before they can be used as the target between-group effect; retain the indirectness of mixed-cohort results. Materials needed: IBD-stratum results table, arm-specific denominators, separate analysis plan and the original S05 excluded-studies table.", "role": "Required", "role_reason": "This is needed to prevent results including IBS from being transferred to a causal effect on IBD fatigue with a specified cause.", "application_exception": "Do not delete the mixed-trial results. Unverified IBD-stratum results do not mean an effect of 0, equivalence or absence of all human research.", "criterion": "Actual separate results and analysis denominators for the IBD stratum are required before they can be used as the target between-group effect; retain the indirectness of mixed-cohort results.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — an individual internal adaptation for directness for the IBD stratum, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "First compare the prespecified IBD analysis in the existing trial and the feasibility of separating the original data; in a separate study, prespecify the IBD diagnosis and causes of fatigue." }, { "item_id": "N06", "question_type": "Population selection", "question": "Can age and fatigue criteria and IBD diagnosis/activity be verified?", "needed": "Distinguish the reported age and fatigue interfering with daily activities from actual IBD diagnosis, activity, anemia/mixed causes and duration. Materials needed: inclusion/exclusion table, IBD diagnosis/assessor, Crohn/UC, activity, anemia and fatigue-duration information.", "role": "Required", "role_reason": "This is needed to avoid assuming identical population selection and applicability solely because the same IBD label is used.", "application_exception": "Do not use the fatigue scale's 2-week recall period as the fatigue-duration threshold for entry.", "criterion": "Distinguish the reported age and fatigue interfering with daily activities from actual IBD diagnosis, activity, anemia/mixed causes and duration.", "basis": "M03 §3.2.1; detailed population criteria are internally designed — an individual internal adaptation for population selection, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the selection table defining IBD type, activity and causes of fatigue, and consider prespecified stratification and representativeness in future comparisons." }, { "item_id": "N07", "question_type": "Baseline B12 status", "question": "Can the serum B12 criterion and functional baseline status both be verified?", "needed": "Verify separately the serum eligibility criterion of ≥150 pmol/L, assay, MMA, homocysteine, holotranscobalamin, folate and anemia status. Materials needed: serum assay, baseline distribution, functional B12/folate, Hb and malabsorption/medication assessment information.", "role": "Required", "role_reason": "This is needed to prevent a single serum criterion from merging deficiency-related fatigue and additional supplementation without deficiency into the same question.", "application_exception": "Meeting the serum criterion does not mean that other functional markers are normal. Hb recovery during treatment of deficiency anemia is a separate endpoint.", "criterion": "Verify separately the serum eligibility criterion of ≥150 pmol/L, assay, MMA, homocysteine, holotranscobalamin, folate and anemia status.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed — an individual internal adaptation for baseline B12 status, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare baseline status separately by test, and prespecify hypotheses about effect modification by status when a new comparison is needed." }, { "item_id": "N08", "question_type": "Molecule and formulation", "question": "Have the actual B12 chemical form, product and single-ingredient composition been verified?", "needed": "Verify the actual chemical form, number of active ingredients, product/manufacturer/batch, physical formulation and release form, and distinguish registry search leads from the formulation actually administered. Materials needed: trial product label/composition, batch, administration manual, protocol and original official registry record.", "role": "Required", "role_reason": "This is needed to prevent different cobalamins or combination products from being treated as the same oral single-agent therapy.", "application_exception": "The absence of named additional ingredients in the original abstract differs from confirmation of a single-ingredient composition in the full text/protocol.", "criterion": "Verify the actual chemical form, number of active ingredients, product/manufacturer/batch, physical formulation and release form, and distinguish registry search leads from the formulation actually administered.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — an individual internal adaptation for molecule and formulation, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the product actually administered with planning documents to separate active ingredients, chemical form and formulation, and design comparisons between preparations as a separate question." }, { "item_id": "N09", "question_type": "Route of administration", "question": "Has oral administration been distinguished from results for other routes?", "needed": "Verify the source for the trial's oral route, and preserve sublingual, intranasal, intramuscular/intravenous and transdermal routes as separate exposures. Materials needed: the original abstract's Objective, administration procedures and actual methods in reports of other routes.", "role": "Required", "role_reason": "This is needed to prevent before-and-after fatigue observations with intranasal or sublingual administration from being converted into oral single-agent comparative results.", "application_exception": "Verification of the oral route does not establish the actual product's absorption, bioavailability or equivalence.", "criterion": "Verify the source for the trial's oral route, and preserve sublingual, intranasal, intramuscular/intravenous and transdermal routes as separate exposures.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — an individual internal adaptation for route of administration, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Link each report's route to the exposure table, and consider a separate design holding compound, population and endpoint constant only when a comparison between routes is requested." }, { "item_id": "N10", "question_type": "Dose and exposure", "question": "Have the nominal daily dose and actual intake and frequency been verified?", "needed": "Verify separately the nominal daily dose, dose at 1 time, daily frequency, adherence/cumulative exposure, dietary/additional B12 and loading/maintenance phases. Materials needed: administration/intake records, dose at 1 time/frequency, adherence, diet/fortified foods/additional B12 and loading/maintenance information.", "role": "Required", "role_reason": "This is needed to prevent a nominal dose from being converted into actual intake or an optimal individual dose.", "application_exception": "Preserve the manuscript's existing record of the conversion 1000 µg=1 mg. Do not newly calculate cumulative exposure or a dose-response relationship.", "criterion": "Verify separately the nominal daily dose, dose at 1 time, daily frequency, adherence/cumulative exposure, dietary/additional B12 and loading/maintenance phases.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — an individual internal adaptation for dose and exposure, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the existing trial's nominal prescription with intake records, and separate a direct dose-response question into a distinct randomized comparison." }, { "item_id": "N11", "question_type": "Placebo comparison", "question": "Can placebo composition and matching be verified?", "needed": "Distinguish the report of placebo control from actual placebo ingredients, physical matching and the comparison between assigned groups. Materials needed: placebo composition/manufacturing table, matching to the active preparation, administration procedures and blinding checks.", "role": "Required", "role_reason": "The placebo label alone cannot establish complete verification of active-ingredient differences and sensory blinding.", "application_exception": "Retain the report of double blinding, and do not turn unverified placebo composition into absence of a placebo.", "criterion": "Distinguish the report of placebo control from actual placebo ingredients, physical matching and the comparison between assigned groups.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M08 §8.1–8.2.3; internal application — an individual internal adaptation for placebo comparison, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the composition, appearance and administration of the actual placebo and active preparation to examine what difference the named comparison introduced." }, { "item_id": "N12", "question_type": "Background treatment", "question": "Have arm-specific IBD management, concomitant treatments and rescue treatment been verified?", "needed": "Verify common IBD management, concomitant medications/diet, rescue treatment, arm-specific changes and their impact on the effect of interest. Materials needed: arm-specific IBD treatments, doses/changes, diet, rescue treatment, additional active ingredients and adherence records.", "role": "Required", "role_reason": "This is needed to prevent differences in IBD management from being attributed to the contribution of added B12.", "application_exception": "The aim of identical background management differs from verified balance in the actual trial. Do not require every change to be identical.", "criterion": "Verify common IBD management, concomitant medications/diet, rescue treatment, arm-specific changes and their impact on the effect of interest.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — an individual internal adaptation for background treatment, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the existing arm-specific management table and analytical handling, and prespecify principles for common management and rescue treatment in subsequent comparisons." }, { "item_id": "N13", "question_type": "Observation time point", "question": "Can the 8-week observation, prespecified primary time point and follow-up scope be verified?", "needed": "Separate the 8 weeks of exposure/measurement from the preregistered primary time-point hierarchy, follow-up after discontinuation and sustained effects. Materials needed: visit/exposure schedule, registration history, protocol/SAP time-point hierarchy and follow-up data.", "role": "Required", "role_reason": "This is needed to prevent a reported time point from being converted into the sole prespecified primary time point or a long-term sustained effect.", "application_exception": "Do not impose an arbitrary minimum long-term duration on this 8-week question.", "criterion": "Separate the 8 weeks of exposure/measurement from the preregistered primary time-point hierarchy, follow-up after discontinuation and sustained effects.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application — an individual internal adaptation for observation time point, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare planned visits with reported results, and design separate follow-up after discontinuation only when sustained effects are requested." }, { "item_id": "N14", "question_type": "CIS definition", "question": "Have the number of subjective-fatigue items, range and direction been preserved?", "needed": "Clearly link the CIS subjective-fatigue total for 8 items, its range of 8–56 points and the direction in which higher scores indicate greater severity. Materials needed: CIS subjective-fatigue definition, trial questionnaire/scoring rules and results tables by time point.", "role": "Required", "role_reason": "This is needed to prevent changes in total CIS or motivation scores from being converted into subjective-fatigue subscale values.", "application_exception": "Verification of the scale definition does not mean that the actual trial language, version and measurement procedures have also been verified.", "criterion": "Clearly link the CIS subjective-fatigue total for 8 items, its range of 8–56 points and the direction in which higher scores indicate greater severity.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application — an individual internal adaptation for the CIS definition, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the scale definition with the actual trial questionnaire/results columns to verify that they use the same score unit." }, { "item_id": "N15", "question_type": "Recall and importance", "question": "Have the 2-week recall period, trial language and important difference in IBD been distinguished?", "needed": "Separate the 2-week recall period from the symptom-duration requirement for entry, and verify the actual language/version and an MCID appropriate to the target between-group estimate. Materials needed: trial language/version, recall instructions and MCID evidence applicable to the between-group effect in IBD.", "role": "Required", "role_reason": "This is needed to prevent thresholds from another disease or scale from being imported to establish the sufficiency or clinical importance of fatigue results.", "application_exception": "Do not turn an unverified MCID into absence of a score definition, or adopt an arbitrary number.", "criterion": "Separate the 2-week recall period from the symptom-duration requirement for entry, and verify the actual language/version and an MCID appropriate to the target between-group estimate.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M15 §15.3.1–15.3.3; internal application — an individual internal adaptation for recall and importance, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the original questionnaire instructions, and separately review anchor-based evidence of importance appropriate to the population and estimate." }, { "item_id": "N16", "question_type": "Endpoint hierarchy", "question": "Has the prespecified hierarchy of CIS fatigue, motivation and other subscales been verified?", "needed": "Distinguish the abstract's designation of fatigue(CIS) as primary from the exact subscale hierarchy, and do not repurpose separate motivation/depression/quality-of-life results. Materials needed: protocol/SAP, results tables by scale and multiplicity/prespecified hierarchy documents.", "role": "Required", "role_reason": "This is needed to prevent selection of a favorable subscale to replace the target subjective-fatigue result.", "application_exception": "Do not delete actual favorable reports for other endpoints because the target fatigue result was nonsignificant; retain their separate attribution.", "criterion": "Distinguish the abstract's designation of fatigue(CIS) as primary from the exact subscale hierarchy, and do not repurpose separate motivation/depression/quality-of-life results.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 Table 8.2.a, M03 §3.2.4; internal application; M08 Table 8.2.a, M04 §4.6.3; internal application — an individual internal adaptation for endpoint hierarchy, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the prespecified hierarchy with all reported subscales, and separate analyses and interpretations by outcome." }, { "item_id": "N17", "question_type": "Allocation and design", "question": "Have the actual randomized design, sequence and allocation concealment been verified?", "needed": "Verify separately the reported randomized placebo-controlled design and actual sequence generation, allocation concealment and baseline balance. Materials needed: original Methods, allocation/concealment procedures, baseline characteristics and analysis-unit table.", "role": "Required", "role_reason": "This is needed to avoid concluding from the RCT label that allocation-related bias or baseline differences have been resolved.", "application_exception": "Do not arbitrarily mark crossover/cluster considerations as inapplicable or reclassify the study as nonrandomized because design details are unavailable.", "criterion": "Verify separately the reported randomized placebo-controlled design and actual sequence generation, allocation concealment and baseline balance.", "basis": "M08 §8.1–8.2.3; internal application; M03 §3.2.1; detailed population criteria are internally designed — an individual internal adaptation for allocation and design, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare existing allocation documents and the baseline table, and apply only assessment questions appropriate to the design." }, { "item_id": "N18", "question_type": "Subjective measurement", "question": "Have blinding, the scale and collection conditions for fatigue measurement been verified?", "needed": "Verify participant/assessor blinding, questionnaire collection and between-arm measurement differences as appropriate to the subjective-fatigue endpoint. Materials needed: questionnaire collection procedures, participant/assessor blinding and placebo matching/blinding checks.", "role": "Required", "role_reason": "This is needed to distinguish differences in measurement of subjective outcomes from actual outcome differences.", "application_exception": "Do not treat the double-blind designation as confirmation of fully maintained blinding, or conclude failure solely because details are unverified.", "criterion": "Verify participant/assessor blinding, questionnaire collection and between-arm measurement differences as appropriate to the subjective-fatigue endpoint.", "basis": "M08 Table 8.2.a, M03 §3.2.4; internal application; M08 §8.1–8.2.3; internal application — an individual internal adaptation for subjective measurement, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare questionnaire/visit conditions and actual blinding to review measurement limitations by endpoint." }, { "item_id": "N19", "question_type": "Allocation and analysis denominators", "question": "Can arm-specific and IBD-stratum analysis denominators also be verified beyond the total of 95 participants?", "needed": "Link the total included separately from arm-specific randomized/completed/analyzed counts and IBD-stratum denominators. Materials needed: CONSORT flow diagram and tables of arm-specific randomized/completed/analyzed counts and IBS/IBD composition.", "role": "Required", "role_reason": "This is needed to avoid dividing the mixed-cohort total in half or assuming that all were analyzed participants with IBD.", "application_exception": "When denominators are unavailable, do not estimate arm-specific counts; preserve only the descriptive total.", "criterion": "Link the total included separately from arm-specific randomized/completed/analyzed counts and IBD-stratum denominators.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — an individual internal adaptation for allocation and analysis denominators, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Link participant flow to denominators in each results table to review differences among randomized, completed and analyzed populations." }, { "item_id": "N20", "question_type": "Missing data and analysis population", "question": "Can ITT/PP, imputation and handling of attrition be verified?", "needed": "Compare reasons for missing data/dropout, ITT/PP, imputation and rescue treatment with the effect of interest in the analysis results. Materials needed: arm-specific dropout reasons, missing-data table, ITT/PP definitions, imputation/SAP and handling of rescue treatment.", "role": "Required", "role_reason": "This is needed to prevent missing denominators from being converted into complete follow-up or an ITT analysis.", "application_exception": "Unverified baseline/analysis details do not mean that there was no attrition in either arm or that bias is established.", "criterion": "Compare reasons for missing data/dropout, ITT/PP, imputation and rescue treatment with the effect of interest in the analysis results.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — an individual internal adaptation for missing data and analysis population, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the original participant flow and analysis definitions, and plan a missing-data sensitivity review within the scope of acquired materials." }, { "item_id": "N21", "question_type": "Original mixed-cohort values", "question": "Can mixed-cohort change values, the definition of ± and the type of values be verified?", "needed": "Preserve the mixed IBS/IBD change values of −8.1 ±9.5 and −8.3 ±10.6 in their original units, without inferring mean/median or SD/SE. Materials needed: original results table, definition of ±, mean/median, baseline/end/change values and arm-specific denominators.", "role": "Required", "role_reason": "This is needed to prevent the displayed ± from being assumed to be SD and used to create precision or a target IBD effect.", "application_exception": "Retain the original values as the corresponding mixed-cohort changes without deleting them. Do not convert them into absolute baseline/end values or a between-group estimate.", "criterion": "Preserve the mixed IBS/IBD change values of −8.1 ±9.5 and −8.3 ±10.6 in their original units, without inferring mean/median or SD/SE.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application — an individual internal adaptation for original mixed-cohort values, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare numerical column headings, dispersion notation and denominators in the table to verify the type of values. Do not newly calculate statistics without authorization." }, { "item_id": "N22", "question_type": "Historical descriptive difference", "question": "Has the existing +0.2-point value been kept from being converted into the target IBD effect?", "needed": "Preserve the manuscript's simple mixed-cohort difference of +0.2 as existing descriptive arithmetic, and distinguish it from the actual adjusted between-group effect and CI. Materials needed: original results table, existing arithmetic record and analysis document specifying the estimand/population/denominators.", "role": "Required", "role_reason": "This is needed to prevent earlier descriptive calculations from being presented as a new calculation in this run or a directly eligible estimate.", "application_exception": "The calculation audit/tools are not executed or separately read in this run. Preserving the original arithmetic value alone does not constitute a claim of reproducibility verification.", "criterion": "Preserve the manuscript's simple mixed-cohort difference of +0.2 as existing descriptive arithmetic, and distinguish it from the actual adjusted between-group effect and CI.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — an individual internal adaptation for the historical descriptive difference, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "In an authorized subsequent review, compare original values with calculation definitions, and keep the descriptive difference and target estimand in separate columns." }, { "item_id": "N23", "question_type": "CI attribution", "question": "Has the estimate corresponding to the 95% CI −11.65~6.71 been verified?", "needed": "Attach a reported CI to an effect only after verifying its population, estimate, denominators and analysis. Materials needed: CI headings in the original Results/tables, corresponding estimate, group/stratum, model and denominators.", "role": "Required", "role_reason": "This is needed to prevent an unattributed CI from being attached as the interval for the existing +0.2 or the IBD-stratum effect.", "application_exception": "Preserve both the original notation and the unverified attribution, without deleting the CI or calculating a new interval.", "criterion": "Attach a reported CI to an effect only after verifying its population, estimate, denominators and analysis.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M15 §15.3.1–15.3.3; internal application; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed — an individual internal adaptation for CI attribution, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the original CI sentence and table to verify which estimand the interval concerns, then interpret it in the same units and at the same time point." }, { "item_id": "N24", "question_type": "Target effect and precision", "question": "Have the IBD-stratum difference in change, CI and P and their relationship to importance been verified?", "needed": "Link the target IBD stratum's between-group estimate, denominators, CI, P and model, and compare them with applicable evidence of importance. Materials needed: adjusted/unadjusted IBD-stratum difference in change, CI/P, model, denominators and target MCID evidence.", "role": "Required", "role_reason": "This is needed to prevent effect size or sufficiency from being inferred solely from total sample size, nonsignificance or an unattributed CI.", "application_exception": "Do not adopt sample-size/duration thresholds or a new grade while the MCID, model and target values remain unverified.", "criterion": "Link the target IBD stratum's between-group estimate, denominators, CI, P and model, and compare them with applicable evidence of importance.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application — an individual internal adaptation for target effect and precision, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "First fix the target estimand and compare the results table with the analysis plan; review importance/precision only against verified criteria." }, { "item_id": "N25", "question_type": "Registration and plan", "question": "Have the candidate registration's actual identity and comparison of the plan with results been verified?", "needed": "Record whether the NL-OMON34980 linkage is confirmed and the actual scope of comparison of the protocol/SAP, subscales/time points and analysis plan. Materials needed: original official registry record/version, protocol/SAP and reported results/reasons for changes.", "role": "Required", "role_reason": "This is needed to avoid claiming that a prior plan is verified solely from a registry search lead, or establishing nonregistration from an access failure.", "application_exception": "Do not repurpose the S04 tablet lead or past access failure as the actual formulation or a current access failure.", "criterion": "Record whether the NL-OMON34980 linkage is confirmed and the actual scope of comparison of the protocol/SAP, subscales/time points and analysis plan.", "basis": "M08 Table 8.2.a, M04 §4.6.3; internal application; M04 §4.5–4.6 principles for collecting/selecting materials; separation of access and reading and the hyperlink contract are internally designed; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application — an individual internal adaptation for registration and plan, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Verify dates/versions of existing registration and plans, and compare the original report's subscales, time points and analyses individually." }, { "item_id": "N26", "question_type": "Nonsignificant results", "question": "Has mixed-cohort nonsignificance been kept from being converted into an IBD effect of 0 or equivalence?", "needed": "Retain the report of nonsignificant subjective fatigue in the mixed cohort, while linking limitations concerning the population, exact P/interval and equivalence design. Materials needed: original Results, exact P, interval, test/equivalence margins and IBD-stratum analysis.", "role": "Required", "role_reason": "This is needed to avoid hiding contrary results or establishing no effect solely from nonsignificance.", "application_exception": "Do not convert nonsignificant subjective fatigue into absence of a separate motivation result.", "criterion": "Retain the report of nonsignificant subjective fatigue in the mixed cohort, while linking limitations concerning the population, exact P/interval and equivalence design.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application — an individual internal adaptation for nonsignificant results, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the direction, population and estimand across all relevant results, and examine equivalence questions using a separate design with prespecified margins." }, { "item_id": "N27", "question_type": "Eligible replication", "question": "Can independent replication results for the target IBD fatigue be verified?", "needed": "Distinguish the verified scope of directly eligible results, related families and requotations, without estimating replication or unique participants. Materials needed: eligible IBD comparative results, unique trial/registration family table and distribution of results by time point/analysis.", "role": "Required", "role_reason": "This is needed to prevent 17 materials or multiple reports of a single trial from being converted into independent replication.", "application_exception": "Do not convert the absence of verified eligible results into absence of heterogeneity across all studies or Not applicable for applicability across conditions.", "criterion": "Distinguish the verified scope of directly eligible results, related families and requotations, without estimating replication or unique participants.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M04 §4.5, §4.6.3; limitations on the current material conversion reflect user-defined scope and internal design — an individual internal adaptation for eligible replication, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "First compare direct eligibility and family identity, and compare differences in conditions/contrary results only when a new independent result is available." }, { "item_id": "N28", "question_type": "Combination-product boundary", "question": "Have the favorable combination-product results in S09 been separated from the effect of B12 alone?", "needed": "Retain the favorable fatigue results for the B-vitamin and magnesium combination in their original report context, without repurposing them as the contribution of B12 alone. Materials needed: S09 actual composition, route, population, fatigue scale, arm-specific results/denominators and design documents.", "role": "Required", "role_reason": "This is needed to prevent results from a trial containing other active ingredients from being attributed to single-ingredient efficacy.", "application_exception": "Do not delete favorable indirect results either. Do not fill in doses, denominators or effect estimates absent from the current stored summary by estimation.", "criterion": "Retain the favorable fatigue results for the B-vitamin and magnesium combination in their original report context, without repurposing them as the contribution of B12 alone.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; separation of statuses is internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application — an individual internal adaptation for the combination-product boundary, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare original combination-product reports by ingredient/population/scale, and consider comparisons separating ingredients when an individual contribution is the question." }, { "item_id": "N29", "question_type": "Reviews and requotations", "question": "Can the original-trial linkages and target IBD results in S05/S08 be verified?", "needed": "Link review inclusion/exclusion and requotation identities to the actual original trials, and distinguish the scope of results retained in the current stored summary. Materials needed: review inclusion/exclusion tables, original-trial linkages and each study's population/intervention/endpoint/results.", "role": "Required", "role_reason": "This is needed to prevent the number of review documents from being converted into a count of new independent effect replications.", "application_exception": "Do not create new results or a unique trial count solely from the S08 location record of Section3.6, Table1 Schlichtiger1996 and reference81.", "criterion": "Link review inclusion/exclusion and requotation identities to the actual original trials, and distinguish the scope of results retained in the current stored summary.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting materials; separation of access and reading and the hyperlink contract are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application — an individual internal adaptation for reviews and requotations, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the linkage table between reviews and original reports to group the same trials/requotations, and separately verify only eligible comparisons." }, { "item_id": "N30", "question_type": "Other fatigue studies", "question": "Have intranasal ME/CFS, sublingual fibromyalgia and protocol materials been separated?", "needed": "Distinguish the different populations, routes and before-and-after observations in S10/S11 and the S12 protocol search identity from the target comparative results. Materials needed: S10/S11 actual populations, administration/analysis and results, and the S12 original protocol and subsequent completed report.", "role": "Required", "role_reason": "This is needed to prevent response observations in other diseases and routes or planning documents from being converted into completed oral IBD RCT results.", "application_exception": "Do not establish the population, product or completed results solely from the S12 search citation. Do not fill in responder counts absent from the current stored summary.", "criterion": "Distinguish the different populations, routes and before-and-after observations in S10/S11 and the S12 protocol search identity from the target comparative results.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M08 §8.2.2, M15 §15.3.1; internal application — an individual internal adaptation for other fatigue studies, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Distinguish population, route, controlled/before-and-after comparison and plan/results for each report in an identity table, and review the eligible IBD question separately." }, { "item_id": "N31", "question_type": "Mechanisms and clinical extension", "question": "Have serum increases, anemia recovery and vitality been kept from replacing CIS fatigue?", "needed": "Distinguish mechanisms, serum B12, Hb/anemia and vitality/other clinical events from the target patient-reported fatigue score. Materials needed: endpoint-specific definitions/original results and direct comparative materials for the proposed extended clinical question.", "role": "Supplementary; required for extended claims", "role_reason": "This is needed to prevent a metabolic role or correction of anemia from being converted into direct benefit for the target fatigue versus placebo.", "application_exception": "Do not require all event trials for the selected symptom-score question; review them separately when a claim is extended.", "criterion": "Distinguish mechanisms, serum B12, Hb/anemia and vitality/other clinical events from the target patient-reported fatigue score.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M03 §3.2.4; internally defined boundaries on extension; M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed — an individual internal adaptation for mechanisms and clinical extension, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Separate current fatigue results from other endpoints, and first define a distinct population, comparator and time frame if an event/anemia/vitality question is requested." }, { "item_id": "N32", "question_type": "Funding and interests", "question": "Has the actual scope of disclosures for funding, product supply and COI been verified?", "needed": "State the actual scope of disclosures and unverified information on funding, product supply, employment/patents and COI. Materials needed: original Funding/COI, product supply, author employment/patents and institutional/trial-family disclosures.", "role": "Supplementary; required for claims of independence", "role_reason": "This is needed to prevent unverified funding from being converted into independent funding or proof of independent replication.", "application_exception": "Do not automatically exclude results because a COI lead exists, or conclude absence of bias because none is available.", "criterion": "State the actual scope of disclosures and unverified information on funding, product supply, employment/patents and COI.", "basis": "Chamgap's internal independence and attribution criteria. The official methods sections used in this pilot do not endorse every detail of this item; M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application — an individual internal adaptation for funding and interests, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare original disclosures with product supply and institutional relationships, record only the verified level, and separate this from replication-family identity." }, { "item_id": "N33", "question_type": "Trial harms and denominators", "question": "Have arm-specific adverse events, serious adverse events, discontinuations and denominators in the oral trial been verified?", "needed": "Verify separately the oral trial's arm-specific AE/SAE/discontinuations due to adverse events, denominators and collection/follow-up. Materials needed: arm-specific AE/SAE/discontinuation tables, person/event counts, exposure denominators, collection methods and losses to follow-up.", "role": "Supplementary; required for safety questions", "role_reason": "This is needed to avoid establishing absence of events or safety simply because safety events are absent from an efficacy summary.", "application_exception": "Do not extend what could not be verified in the original abstract to nonreporting throughout the full article. Do not delete original efficacy values because of gaps in harms information.", "criterion": "Verify separately the oral trial's arm-specific AE/SAE/discontinuations due to adverse events, denominators and collection/follow-up.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed distinctions are internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; design-specific adaptations are internally designed — an individual internal adaptation for trial harms and denominators, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare original safety collection with events/persons and denominators, and prespecify systematic collection, discontinuation reasons and losses to follow-up in future comparisons." }, { "item_id": "N34", "question_type": "UL and general safety", "question": "Has the absence of an established UL for B12 been kept from being converted into an unlimited safety guarantee?", "needed": "Distinguish the scope of official B12 safety/status and medication documents from direct trial harms data. Materials needed: the relevant S13 safety/status/medication sections and direct harms data by exposure and population.", "role": "Supplementary; required for extensions of safety claims", "role_reason": "This is needed to prevent water solubility or the absence of a UL from being converted into safety evidence for a particular high oral dose, population or duration.", "application_exception": "An official-document link or historical reading record does not constitute access to the official original in this run or verification of the trial's event rate.", "criterion": "Distinguish the scope of official B12 safety/status and medication documents from direct trial harms data.", "basis": "M19 §19.1.2–19.2.4; internal application; Chamgap's internal interpretive boundaries. M19 principles are referenced; no official causality tool is implemented — an individual internal adaptation for UL and general safety, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the scope of judgments in official documents with the direct trial's population, duration and collection methods; consider suitable separate designs for rare and long-term harms." }, { "item_id": "N35", "question_type": "Cobalt and chemical form", "question": "Have the chemical forms covered by the cobalt-sensitivity notice been preserved?", "needed": "Distinguish the official notice concerning hydroxocobalamin and cyanocobalamin from the oral trial whose actual chemical form is unverified. Materials needed: preparations/exposures covered by the S14 official notice, the actual trial chemical form and allergy eligibility/event data.", "role": "Supplementary; required for the relevant scope of harms", "role_reason": "This is needed to prevent a warning for a particular chemical form from being converted into confirmed events or incidence in this trial.", "application_exception": "Do not interpret an unverified chemical form as meaning there is no cobalt sensitivity.", "criterion": "Distinguish the official notice concerning hydroxocobalamin and cyanocobalamin from the oral trial whose actual chemical form is unverified.", "basis": "M19 §19.1.2–19.2.4; internal application; M19 §19.2.2–19.2.4 design considerations; detailed confounding records are internally designed; Chamgap's internal interpretive boundaries. M19 principles are referenced; no official causality tool is implemented; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — an individual internal adaptation for cobalt and chemical form, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare preparations and exposures in the notice with the trial product to review applicability, and separate allergy/alternative explanations in the harms record." }, { "item_id": "N36", "question_type": "Injection-label boundary", "question": "Have the injectable product's Leber and hypokalemia warnings been separated from oral incidence?", "needed": "Preserve the disease, treatment phase and route in the cyanocobalamin injection label as in the manuscript, without repurposing them as oral-trial harms. Materials needed: S15 label Contraindications/Warnings, the context of testing early in treatment and actual oral-preparation/harms data.", "role": "Supplementary; required for extensions of safety claims", "role_reason": "This is needed to prevent warnings in the context of injections and intensive anemia treatment from being converted into causality/frequency for another oral exposure.", "application_exception": "Do not delete the warnings or add incidence or individual dosing instructions.", "criterion": "Preserve the disease, treatment phase and route in the cyanocobalamin injection label as in the manuscript, without repurposing them as oral-trial harms.", "basis": "M19 §19.1.2–19.2.4; internal application; Chamgap's internal interpretive boundaries. M19 principles are referenced; no official causality tool is implemented; M03 §3.2.2–3.2.3; reverse-direction labeling and test adaptations are internally designed — an individual internal adaptation for the injection-label boundary, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Compare the official label's route, disease and treatment phase with the target exposure to distinguish the scope of harms warnings." }, { "item_id": "N37", "question_type": "Extension to longer durations and vulnerable groups", "question": "Are long-term, vulnerable-group and optimal-dose data required for this 8-week fatigue question?", "needed": "Distinguish questions about long-term/rare harms, pregnancy/lactation/children, liver/kidney disease, optimal dose and individual management from the current scope. Materials needed: data on the population/duration/direct dose/follow-up after discontinuation proposed for extension, systematic harms data and separate clinical-question materials.", "role": "Supplementary; required for extended claims", "role_reason": "This is a supplementary boundary to prevent short-term reports in a restricted population from being converted into overall safety and dosing recommendations.", "application_exception": "Do not require every long-term/vulnerable-group/dose study for the reported 8-week fatigue question.", "criterion": "Distinguish questions about long-term/rare harms, pregnancy/lactation/children, liver/kidney disease, optimal dose and individual management from the current scope.", "basis": "M03 §3.2.1–3.2.4; details of dose, persistence and effect modification are internally designed; M19 §19.1.2–19.2.4; internal application; Chamgap's internal interpretive boundaries. M19 principles are referenced; no official causality tool is implemented — an individual internal adaptation for extension to longer durations and vulnerable groups, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "Define a separate population, exposure and follow-up/comparison only when an extended question is requested, and consider suitable observational/comparative designs for rare/long-term harms." }, { "item_id": "N38", "question_type": "Original assessment and calculation history", "question": "Have 0 directly eligible results, the existence of human research, ?/null and the legacy gate been separated?", "needed": "Preserve unchanged the original grade/score, factual profile, null downstream axes and record of the legacy nonempirical gate projection, without generating a new status or score. Materials needed: the current original assessment, original scoring inputs/diagnostics, separate gate projection and existing calculation record.", "role": "Required", "role_reason": "This is needed to prevent unverified direct eligibility from being converted into no_human_study=true, or document quality/historical calculations from being inherited as an efficacy score.", "application_exception": "The S17 sealed audit and calculator are not read or executed in this run. Do not fill a null scoring axis with the conceptual symptom P.", "criterion": "Preserve unchanged the original grade/score, factual profile, null downstream axes and record of the legacy nonempirical gate projection, without generating a new status or score.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; question-specific outcome adaptations are internally designed; M04 §4.5, §4.6.3; limitations on the current material conversion reflect user-defined scope and internal design — an individual internal adaptation for original assessment and calculation history, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "When an authorized correction is needed, separate the factual profile, compatibility mapping and calculation event, and preserve before/after values and reasons. No reassessment is performed in this run." }, { "item_id": "N39", "question_type": "Operational metadata and updates", "question": "Have original ID/URL, document quality and deployment metadata been distinguished from completion of the current table?", "needed": "Preserve the current canonical/ID and historical operational metadata, and separately record actual completion of content/format/UI/publication and update events. Materials needed: original identity/operational metadata, actual publication records and revision triggers/original-version preservation records.", "role": "Required", "role_reason": "This is needed to prevent document A, past self-review and deployment labels from being converted into clinical certification or completed publication of the current table.", "application_exception": "Do not silently reconcile semantic_code_status and assigned labels, or server_deployed and initial unpublished/null time records, even when they coexist.", "criterion": "Preserve the current canonical/ID and historical operational metadata, and separately record actual completion of content/format/UI/publication and update events.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5, §4.6.3; limitations on the current material conversion reflect user-defined scope and internal design; M04 §4.5–4.6 principles for collecting/selecting materials; separation of access and reading and the hyperlink contract are internally designed — an individual internal adaptation for operational metadata and updates, not implementation of or certification by an official assessment tool.", "condition_origin": "An individually developed criterion designed with knowledge of the currently retained 3114 content. It is neither blinded nor a new clinical preregistration.", "proposed_research": "When operational facts are updated, compare actual records with original metadata, and distinguish criterion revisions, evidence additions and output/publication events." } ] }