{ "schema_version": "chamgap-public-criteria-1.0", "title": "Folic acid × Increase in source-defined category-a progressive motility in male-factor infertility", "criteria_version": "NGM-v3110-FOLIC15-CATEGORYA-M3-1.0", "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": "Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools." }, { "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": "Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools." }, { "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": "Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools." }, { "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": "Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools." }, { "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": "Comparison of the 5 raw-byte copies and SHAs of the methods HTML for 1585, and historical reuse of the principles from that time. This is not new reading of full methodological texts or application/certification of official tools." } ], "status_dictionary": { "Met": "The relevant narrow recording criterion has been met, such as the exact question, attribution of numbers/historical calculations, reading or version. This is not certification of clinical efficacy/safety or verification of external full texts in this task.", "Partly verified": "Relevant retained reports are available, but some comparisons with original methods, plans, denominators, intervals, identities or access needed for the criterion remain outstanding.", "Unverified": "The necessary values/materials could not be established within the currently retained inputs and the scope of verification at the time. This does not mean an effect of 0 or absence of studies worldwide.", "Not reported": "Used only for the scope of nonreporting in materials/sections actually read or in explicitly identified historical summaries. It is not extended to the entirety of external full texts not read in this task.", "Conflicting information": "Each row identifies a retained discrepancy/candidate error concerning the same fact or a difference in publication metadata. Mere numerical differences arising from different questions or endpoint/change values are not labeled as conflicts.", "Inaccessible": "Used only when actual external access fails in the present task. Because access was not attempted here, historical failures are not transferred to the current status.", "Review incomplete": "The scope of review actually remaining or external materials not yet compared in the present task. This does not mean that the entire already completed review of retained stored summaries is incomplete.", "Not applicable": "Limited to establishing optimal dose, long-term/special-population outcomes or personal safety outside the current narrow M3 category-a question. It is not a substitute for materials not read or certification of safety." }, "requirements": [ { "item_id": "N01", "question_type": "Separate question", "question": "Which distinct comparison of population, exposure, comparator and endpoint is addressed?", "needed": "The original claim; the identity of the population, single added ingredient, comparator and M3 change endpoint, and the boundaries of exclusion", "role": "Required", "role_reason": "This is needed to avoid combining all male infertility, semen parameters and pregnancy outcomes into the judgment of one table merely because they share the ingredient name folic acid.", "application_exception": "The current subclaims array is empty. No additional main tables are created for other doses, pregnancy or live birth.", "criterion": "Preserve the original /ko/effect unchanged and link it to the single question of 15 mg/day, M3−M0, source-defined category a and matched placebo.", "basis": "C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; 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 adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E09: M03 §3.2.4; internally defined boundaries for extending the claim. Reason for applying this in this case: This is needed to avoid combining all male infertility, semen parameters and pregnancy outcomes into the judgment of one table merely because they share the ingredient name folic acid. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the elements of the question in the current manuscript and structure, and separate other questions such as PR, a+b and pregnancy in the boundary records." }, { "item_id": "N02", "question_type": "Identity of the main trial", "question": "By which identifiers are the FOLFIV article, index record and registration linked?", "needed": "Identifiers and report types/locations for the S01 article, S02 index record and S03 registration", "role": "Required", "role_reason": "This is needed to avoid counting the PDF, PubMed record and registration of the same trial as evidence replicated three times.", "application_exception": "Verification of the NCT identifier does not establish verification of the complete registration history or the plan for the relevant outcome.", "criterion": "Link the DOI, PMID, PMCID, NCT and report types in the current bibliography, while retaining limitations on access to original sources.", "basis": "C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed. Reason for applying this in this case: This is needed to avoid counting the PDF, PubMed record and registration of the same trial as evidence replicated three times. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the identifiers and related reports, group them into one trial family, and separately record the lack of comparison against the registration text/history." }, { "item_id": "N03", "question_type": "Study families and missing references", "question": "Have overlap and missing references in the report list and study families been distinguished?", "needed": "The actual bibliography, the families and linked-source lists in the evidence, and materials linked as S15/S16", "role": "Required", "role_reason": "This is needed to avoid adding the main trial, correction and index records as independent samples or inventing sources that were not provided.", "application_exception": "The current inputs do not contain sources/trial_families/detailed numerical arrays. References to S15/S16 in the evidence are not issued as separate actual reports.", "criterion": "Preserve the links between the actual 14 bibliographic entries and 6 evidence families, and identify references for which bibliographic information was not provided.", "basis": "C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid adding the main trial, correction and index records as independent samples or inventing sources that were not provided. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the shared families of S01/S02/S03, S07/S14 and S09/S10, and leave missing references on a list awaiting identity verification." }, { "item_id": "N04", "question_type": "Current and historical reading", "question": "Have the stored summaries read in the present task been distinguished from historical external access?", "needed": "The access_level/locations of each bibliographic entry, the overall review date, the actual reading scope in this task and safe URLs", "role": "Required", "role_reason": "This is needed to avoid upgrading historical full_text records, access failures or links to full-text reading or access failure in the present task.", "application_exception": "verified_date is the overall evidence review date. Because there is no per-report access-date key, it is not used as an actual access date.", "criterion": "Separate reading of the currently stored summaries from external material types that were not accessed, acquired or read, and leave historical access dates empty.", "basis": "C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid upgrading historical full_text records, access failures or links to full-text reading or access failure in the present task. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Transfer each bibliographic access level as a historical record, and separately cross-check the current material-type statuses, dates and link types." }, { "item_id": "N05", "question_type": "Scope of search and correction checks", "question": "At which cutoff date and within which verification scope are evidence and corrections discussed?", "needed": "The search/review record dated 2026-09-16, the actual S10 correction and revision_triggers", "role": "Required", "role_reason": "This is needed to avoid exaggerating the retained search scope into an up-to-date search of all literature or an absence of studies worldwide.", "application_exception": "Even though the corrections array is empty, the Korean manuscript and S10 contain the FAZST correction. The empty array is not used to mean that there are no corrections.", "criterion": "Distinguish the evidence cutoff, current review date and historical search scope from the absence of a current comparison for corrections/retractions.", "basis": "C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid exaggerating the retained search scope into an up-to-date search of all literature or an absence of studies worldwide. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the retained search/correction records against the empty structured array, and limit statements about absence and currency without conducting a new search." }, { "item_id": "N06", "question_type": "Ingredient identity", "question": "Which folate form is the trial's active ingredient?", "needed": "Trial ingredient specifications and materials verifying the salt, crystal form and manufacturing source", "role": "Required", "role_reason": "This is needed to avoid substituting dietary folate, 5-MTHF, folinic acid or folic acid plus zinc for the results of folic acid alone.", "application_exception": "Even when the ingredient name is the same, the exact salt and crystal form remain unverified in the current materials.", "criterion": "Distinguish folic acid as the sole randomized added active ingredient from unknown chemical details.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed. Reason for applying this in this case: This is needed to avoid substituting dietary folate, 5-MTHF, folinic acid or folic acid plus zinc for the results of folic acid alone. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the trial ingredient designation against the original specifications, and separate other folate forms/combined active ingredients as different exposures." }, { "item_id": "N07", "question_type": "Product and placebo formulation", "question": "Which formulation details of the tablets and matched placebo are known?", "needed": "Specifications for the Bailly-Creat trial tablets and placebo: release formulation, batch, purity and excipients", "role": "Required", "role_reason": "This is needed to avoid turning the manufacturer's name or the 5 mg designation into certification of the equivalence or quality of all products.", "application_exception": "The 5 mg SmPC of another company is not evidence for the batch or excipients of these Bailly-Creat trial tablets.", "criterion": "Separate tablet count, manufacturer and matching appearance from unverified release formulation, purity, batch and excipients.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid turning the manufacturer's name or the 5 mg designation into certification of the equivalence or quality of all products. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the article and product-supply specifications without automatically transferring information about a different authorized product to this trial product." }, { "item_id": "N08", "question_type": "Route of administration", "question": "What was the actual route of administration?", "needed": "The original designation of the trial's oral route", "role": "Required", "role_reason": "This is needed to avoid extending oral-tablet results to injection, other routes or food exposures.", "application_exception": "This item does not adjudicate the absence of evidence or lack of efficacy for other routes.", "criterion": "Align the oral-route designation in the current manuscript and actual_trial_fields.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed. Reason for applying this in this case: This is needed to avoid extending oral-tablet results to injection, other routes or food exposures. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the original exposure-route designation and limit it to the conditions of the comparison in this table." }, { "item_id": "N09", "question_type": "Nominal dose and actual intake", "question": "Can the planned 15 mg/day regimen be distinguished from actual intake?", "needed": "Originally prescribed tablet count and dose, actual adherence/intake records and total dietary folate", "role": "Required", "role_reason": "This is needed to avoid presenting the assigned dose as every participant's actual intake or the optimal dose.", "application_exception": "3 tablets of 5 mg and a total of 15 mg/day are values in the original materials. No new conversion or dosing recommendation is created.", "criterion": "Distinguish the verification levels for the planned dose, actual dosing times, adherence and dietary exposure.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations 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 on dose, duration and effect modification are internally designed. Reason for applying this in this case: This is needed to avoid presenting the assigned dose as every participant's actual intake or the optimal dose. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Compare nominal assignment with individual intake records, and distinguish adherence analyses according to their analytical purpose and population." }, { "item_id": "N10", "question_type": "Assessment time and exposure duration", "question": "Are the M3 semen assessment and the full treatment/pregnancy follow-up periods the same?", "needed": "Actual timing records for M0/M3 semen assessment, treatment discontinuation, semen collection for IVF and pregnancy follow-up", "role": "Required", "role_reason": "This is needed to avoid turning the 3-month semen endpoint into the full observation period for pregnancy outcomes or every participant's total treatment duration.", "application_exception": "Treatment could continue until semen collection for IVF. No new estimate of a sustained effect after treatment cessation is made.", "criterion": "Distinguish the M3−M0 timing from possible continuation of treatment and the different pregnancy follow-up period.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / H02: M19 §19.2 harm questions by study design; details of temporal relationships are internally designed. Reason for applying this in this case: This is needed to avoid turning the 3-month semen endpoint into the full observation period for pregnancy outcomes or every participant's total treatment duration. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Record the timeline by separately cross-checking the measurement time of each endpoint and the start/end of exposure." }, { "item_id": "N11", "question_type": "Actual male eligibility criteria", "question": "Which men were selected, and did they all have the same motility impairment?", "needed": "Male inclusion/exclusion criteria and the distribution of age and abnormal semen parameters", "role": "Required", "role_reason": "This is needed to avoid treating all IVF partners with at least one semen abnormality as having the same OAT or isolated motility disorder.", "application_exception": "Preserve the article's WHO 2010 designation and criteria as written; do not replace them with modern criteria.", "criterion": "Explain the age range, IVF setting, requirement for at least one abnormal semen parameter and limitations of the mixed eligibility criteria.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed. Reason for applying this in this case: This is needed to avoid treating all IVF partners with at least one semen abnormality as having the same OAT or isolated motility disorder. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check eligibility criteria against the distribution of actual baseline characteristics, recording the narrow applicable population and unverified mixed composition." }, { "item_id": "N12", "question_type": "Deficiency, B12 and genotype", "question": "Are baseline folate-deficiency, B12 and MTHFR status known?", "needed": "Serum folate criteria, baseline deficiency counts, B12/MTHFR distributions and prespecified subgroup plans", "role": "Required", "role_reason": "This is needed to avoid mixing effects of correcting deficiency with supplementation effects in people without deficiency or genotype-specific effects.", "application_exception": "An unverified deficiency count is not filled in as 0 deficient participants or as all participants being deficient.", "criterion": "Separate the serum-deficiency definition from the unverified actual baseline distribution and subgroup effects.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / H08: M19 §19.1.2–19.2.4; internal application. Reason for applying this in this case: This is needed to avoid mixing effects of correcting deficiency with supplementation effects in people without deficiency or genotype-specific effects. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check baseline status against planned subgroup/interaction analyses without transferring genotype findings from the separate Huang trial." }, { "item_id": "N13", "question_type": "Female causes and couples with mixed causes", "question": "Does the description of excluding female causes agree with the baseline table of mixed causes?", "needed": "Female inclusion/exclusion criteria, the baseline table of causes and an explanation/correction of the discrepancy", "role": "Required", "role_reason": "This is needed to avoid deleting female factors in the couples and extending the findings to an effect in purely male-factor infertility.", "application_exception": "Do not silently resolve the conflict between the original methods and baseline table by creating new inclusion criteria.", "criterion": "Preserve female age, the exclusion description and the discrepancy involving mixed causes in 18/17 participants, and explain the limitation on applicability.", "basis": "C04: M03 §3.2.1; detailed population criteria are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid deleting female factors in the couples and extending the findings to an effect in purely male-factor infertility. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the same cause classification in the methods and baseline table, updating the discrepancy only if an explanation or correction from the original authors is available." }, { "item_id": "N14", "question_type": "Actual comparator", "question": "Against what shared background care was the placebo compared?", "needed": "Actual specifications of the matched placebo and background IVF care", "role": "Required", "role_reason": "This is needed to avoid equating the placebo comparison with the natural course under no treatment.", "application_exception": "A shared IVF care policy in both arms does not establish that every individual's treatment was identical.", "criterion": "Display both the 3 matched placebo tablets/day and background IVF-ICSI care in the two arms.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid equating the placebo comparison with the natural course under no treatment. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Distinguish the added active ingredient from common treatment to prevent extension to no treatment or a different comparator." }, { "item_id": "N15", "question_type": "Concomitant treatment and deviations", "question": "Have IVF treatment and other male medications been distinguished from the added trial ingredient?", "needed": "IVF/female stimulation regimens by arm, concurrent male treatment, rescue treatment and handling of deviations", "role": "Required", "role_reason": "This is needed to avoid automatically attributing differences in female stimulation regimens or other treatments to the contribution of folic acid in men.", "application_exception": "The reported absence of male hormonal/vitamin treatment does not mean independent verification in this task or the absence of all concomitant exposures.", "criterion": "Explain the common policy, differences in individual treatments, and the reporting scope and unverified information about other male interventions.", "basis": "E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / H05: M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed. Reason for applying this in this case: This is needed to avoid automatically attributing differences in female stimulation regimens or other treatments to the contribution of folic acid in men. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check concomitant-treatment/change records by arm against the effect of interest, and distinguish female background factors for pregnancy endpoints from semen change." }, { "item_id": "N16", "question_type": "Endpoint, direction and units", "question": "The selected value represents change at which time, in which sperm category and in which units?", "needed": "The label, time, units and direction of the effect of interest for the selected Table4 row", "role": "Required", "role_reason": "This is needed to avoid mixing endpoint percentages, total motility, changes and %/%p.", "application_exception": "Setting higher values as the proposed direction of benefit does not establish clinical importance or actual improvement.", "criterion": "Link Progressive motility (a), M3−M0, percentage point and the original direction of benefit.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid mixing endpoint percentages, total motility, changes and %/%p. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the row label and change/endpoint columns, labeling the time and units of each value separately." }, { "item_id": "N17", "question_type": "Correspondence to WHO classifications", "question": "Can source-defined category a be mapped to modern WHO aggregate PR?", "needed": "The original motility-classification/speed criteria and the relevant definition section in the cited WHO edition", "role": "Required", "role_reason": "This is needed to avoid converting historical sperm classifications merely because they use the same terminology.", "application_exception": "Verification of metadata for WHO edition 6 or a record of failed access to edition 5 alone does not establish verification of definitions/speed criteria.", "criterion": "Retain the unverified correspondence between source category a and a+b/aggregate PR, and the unverified speed criteria, without automatic conversion.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid converting historical sperm classifications merely because they use the same terminology. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the trial's classification rules against the definitions in the actual relevant WHO edition, recording only verified correspondences." }, { "item_id": "N18", "question_type": "Specimen collection and measurement procedures", "question": "What were the actual abstinence, specimen-collection and motility-reading procedures?", "needed": "Semen-collection conditions, motility equipment/reading rules, assessors/blinding and measurement differences between arms", "role": "Required", "role_reason": "This is needed to avoid transferring fixation/freezing methods or reader counts from DNA testing to motility assessment.", "application_exception": "The 2 readers used for DNA assessment are not evidence of the number or blinding of motility assessors.", "criterion": "Distinguish collection after 3–5 days of abstinence from the assessment procedures and limitations specific to motility.", "basis": "E03: M08 Table 8.2.a, M03 §3.2.4; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid transferring fixation/freezing methods or reader counts from DNA testing to motility assessment. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the semen-motility and DNA-testing sections separately, using only information that applies to the actual motility measurement." }, { "item_id": "N19", "question_type": "Endpoint hierarchy and advance planning", "question": "Does the page's primary endpoint match the endpoint hierarchy in the article and registration?", "needed": "The complete NCT01407432 version history, protocol, SAP and records of endpoint/analysis changes", "role": "Required", "role_reason": "This is needed to avoid presenting a category-a row selected after reading the literature as a preregistered primary endpoint.", "application_exception": "Failure to obtain the registration/plans does not establish nonregistration or selective reporting.", "criterion": "Distinguish the article's secondary endpoint and the page's primary endpoint from the unverified prespecified hierarchy, and disclose when the editorial boundaries were selected.", "basis": "E06: M08 Table 8.2.a, M04 §4.6.3; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid presenting a category-a row selected after reading the literature as a preregistered primary endpoint. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Compare the planned endpoints, times and analyses in the registration/protocol with the Table4 report, recording changes or the scope not compared." }, { "item_id": "N20", "question_type": "Design and allocation", "question": "To what extent are the actual parallel-group design and randomization procedures known?", "needed": "Methods/tables for allocation-sequence generation, concealment, personnel responsible and baseline balance between arms", "role": "Required", "role_reason": "This is needed to avoid claiming that all details of allocation sequence, concealment and baseline balance have been verified merely from the RCT label.", "application_exception": "The trial is explicitly described as parallel-group in the current materials. Absence of crossover/cluster adjustment is not turned into a new defect in this design.", "criterion": "Distinguish the description of a double-blind parallel randomized trial from the actual level of verification of allocation procedures.", "basis": "E01: M08 §8.1–8.2.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid claiming that all details of allocation sequence, concealment and baseline balance have been verified merely from the RCT label. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the Methods, flow diagram and baseline tables against allocation procedures, without filling in unverified concealment details." }, { "item_id": "N21", "question_type": "Maintenance of blinding", "question": "Were matched placebo and double blinding actually maintained through assessment and analysis?", "needed": "Blinding of participants, personnel, motility assessors/analysts, and checks of unblinding or successful treatment guesses", "role": "Required", "role_reason": "This is needed to avoid automatically extending matching appearance into verification that assessor/analyst blinding was maintained.", "application_exception": "Unverified blinding details are not labeled as confirmed absence of blinding or automatic failure.", "criterion": "Separate nominal double blinding and matched placebo from gaps in information on who was actually blinded and whether blinding was broken.", "basis": "E01: M08 §8.1–8.2.3; internal application / E03: M08 Table 8.2.a, M03 §3.2.4; internal application / E02: M03 §3.2.3, M08 §8.2.2–8.2.3; internal application. Reason for applying this in this case: This is needed to avoid automatically extending matching appearance into verification that assessor/analyst blinding was maintained. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check who was blinded and records of actual maintenance/breaking of blinding against measurement and analysis of the selected semen endpoint." }, { "item_id": "N22", "question_type": "Allocation, visit and analysis denominators", "question": "Does each number count people allocated, attending a visit, included in change analysis or included in endpoint analysis?", "needed": "The Figure3 flow and person counts in the baseline, M3 and change columns of Table4", "role": "Required", "role_reason": "This is needed to avoid using the total of 162 participants or visit counts as the denominator for the selected change analysis.", "application_exception": "Person counts are not treated as sperm-cell counts or repeated-specimen counts. Means from different populations are not subtracted.", "criterion": "Link each denominator separately: 83/79 allocated, 76/72 attending visits, 66/60 in change analysis and 67/62 in endpoint analysis.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid using the total of 162 participants or visit counts as the denominator for the selected change analysis. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the denominators for each stage/endpoint column, recording allocated, measured and analyzed populations separately." }, { "item_id": "N23", "question_type": "Missing data and the scope of ITT", "question": "How can missing data in the change analysis and the reference to ITT be interpreted?", "needed": "Reasons for missing endpoint data, losses by assigned arm, imputation rules, analysis populations and sensitivity analyses", "role": "Required", "role_reason": "This is needed to avoid turning a statement of the ITT principle into an analysis of all randomized participants in the selected row.", "application_exception": "Unverified missing-data sensitivity is a current evidence gap. The direction or magnitude of missing-data effects is not newly estimated, and no additional score is assigned.", "criterion": "Distinguish the complete paired data for 66/60 participants in the selected row from unverified imputation/sensitivity analyses.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design 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. Reason for applying this in this case: This is needed to avoid turning a statement of the ITT principle into an analysis of all randomized participants in the selected row. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the population and missing-data rules for the selected category-a change row against the Methods/plans and flow, recording the limitations of the assignment effect and complete-case results." }, { "item_id": "N24", "question_type": "Reported main result values", "question": "What are the mean, SD, median, IQR and P value for change in source-defined category a?", "needed": "Mean (SD), median/IQR, test, P value and original denominators for the selected change row in Table4", "role": "Required", "role_reason": "This is needed to avoid substituting different summary statistics or types of dispersion, or equating nonsignificance with an effect of 0.", "application_exception": "The estimands of the mean difference and rank test are not assumed to be identical. SD is not converted into SE or a CI.", "criterion": "Preserve the original values and direction of both arms' change means (SDs), medians/IQRs and the between-arm test.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid substituting different summary statistics or types of dispersion, or equating nonsignificance with an effect of 0. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the columns/units of each statistic and the location of the between-arm test, separating interpretation of means, distribution summaries and significance." }, { "item_id": "N25", "question_type": "Historical arithmetic and endpoint values", "question": "Has historical arithmetic on means been distinguished from the formal between-arm estimator?", "needed": "Existing arithmetic records, their respective change/endpoint columns and the formal test definition", "role": "Required", "role_reason": "This is needed to avoid treating the descriptive arithmetic of −0.2 %p and the endpoint difference of +0.6 %p as the same change effect.", "application_exception": "Both arithmetic values are quotations from the existing manuscript. No new calculation, adjustment, standardized effect, NNT or CI is produced.", "criterion": "Explain the different meanings of historical arithmetic on change means, endpoint means/arithmetic and the formal test.", "basis": "C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E04: M08 §8.2.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid treating the descriptive arithmetic of −0.2 %p and the endpoint difference of +0.6 %p as the same change effect. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the attribution of arithmetic already in the manuscript against the change/endpoint columns, and preserve it as historical material distinct from a new analysis." }, { "item_id": "N26", "question_type": "Between-arm test and effect of interest", "question": "What does P = 0.7871 compare, and which effect estimates are unverified?", "needed": "Definitions of the between-arm test, analysis population, effect of interest and formal estimator for the selected row", "role": "Required", "role_reason": "This is needed to avoid turning a between-arm P value into within-arm improvement or a CI for the mean difference.", "application_exception": "A nonparametric test result is not presented as equivalent to an adjusted effect on means or an adherence effect.", "criterion": "Separate the between-arm Wilcoxon–Mann–Whitney comparison of change from the unverified formal/adjusted effect estimates.", "basis": "E04: M08 §8.2.2, M15 §15.3.1; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid turning a between-arm P value into within-arm improvement or a CI for the mean difference. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the test and analysis population in the Methods/plans and Table4, distinguishing between-arm/within-arm comparisons and assignment/adherence effects." }, { "item_id": "N27", "question_type": "Intervals and precision", "question": "What range of benefits can be assessed using a reported formal between-arm CI?", "needed": "The formal between-arm effect estimate/CI, dispersion, denominators and estimation method for the selected category-a change", "role": "Required", "role_reason": "This is needed to avoid inventing a narrow CI or exclusion of meaningful benefit from SD, sample size or nonsignificance alone.", "application_exception": "The 95.1% CI from FAZST is for a different combination and total motility; it does not substitute for the CI of this row.", "criterion": "Retain the null CI for the direct question and the reason precision cannot be interpreted.", "basis": "C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / E05: M15 §15.3.1–15.3.3; internal application. Reason for applying this in this case: This is needed to avoid inventing a narrow CI or exclusion of meaningful benefit from SD, sample size or nonsignificance alone. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Verify only effect intervals actually reported in the original results/plans; do not reconstruct a new CI from SD in this case." }, { "item_id": "N28", "question_type": "Threshold for an important difference", "question": "Is there an MCID applicable to this category a, population and time point?", "needed": "A validated threshold for important change and its validation context for this source-defined category, population and M3 time point", "role": "Required", "role_reason": "This is needed to avoid declaring criteria met or therapeutic value based on arbitrary minimum changes, participant counts or trial counts.", "application_exception": "Pregnancy-event trials are not unconditionally imposed as mandatory for the question about motility change itself.", "criterion": "Retain the null applicable MCID and the limitation on interpreting clinical importance.", "basis": "E05: M15 §15.3.1–15.3.3; internal application / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid declaring criteria met or therapeutic value based on arbitrary minimum changes, participant counts or trial counts. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the threshold's fit to the population, scale and time point; if no verified threshold is available, keep importance unverified." }, { "item_id": "N29", "question_type": "Positive adjacent evidence", "question": "Have Huang's different dose/genotype results and the conflicting test descriptions been preserved?", "needed": "Huang Table3/footnote and text, genotype-specific motility analysis denominators, tests/CIs and prespecified subgroup plans", "role": "Required", "role_reason": "This is needed to avoid concealing favorable adjacent results or combining them with the category-a effect at 15 mg.", "application_exception": "The 769 eligible participants are not used as the denominator for TT motility analysis, and overlapping genotype strata are not summed.", "criterion": "Retain together the 0.8 mg/day dose, TT genotype, original baseline/endpoint values, conflict between the table footnote and text about the test, and unverified between-arm CI/P value/denominators.", "basis": "C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed. Reason for applying this in this case: This is needed to avoid concealing favorable adjacent results or combining them with the category-a effect at 15 mg. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the within-arm/between-arm attribution of the tests in the table footnote and text, and organize differences in dose, genotype and definition by family." }, { "item_id": "N30", "question_type": "Another single-ingredient dose", "question": "What adjacent information does da Silva's 5 mg single-ingredient result provide?", "needed": "da Silva's single-ingredient-arm results/denominators, motility definition, initial allocation and funding scope", "role": "Required", "role_reason": "This is needed to avoid turning a finding of no difference at another dose and for an a+b endpoint into repeated refutation of the exact category-a question.", "application_exception": "The 49 protocol completers are not used as the initial allocation count.", "criterion": "Distinguish 5 mg/day, 3 months, the older a+b definition and the difference between completion/allocation denominators from the direct question.", "basis": "E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C04: M03 §3.2.1; detailed population criteria are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed. Reason for applying this in this case: This is needed to avoid turning a finding of no difference at another dose and for an a+b endpoint into repeated refutation of the exact category-a question. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the dose, motility definition and analysis population of the adjacent trial separately, avoiding aggregation into the direct category-a change." }, { "item_id": "N31", "question_type": "Single-ingredient candidates in factorial and 4-arm trials", "question": "What remains unknown while the folic-acid-only arms of Wong and Raigani are retained?", "needed": "Endpoints, denominators and quantitative results for each single-ingredient arm in Wong's fertile/subfertile strata and Raigani's 4-arm trial", "role": "Required", "role_reason": "This is needed to avoid discarding an entire 4-arm trial as a combination trial or filling unverified single-ingredient effects with figures from the entire trial.", "application_exception": "Unverified progressive-motility estimators for the individual single-ingredient arms are not described as absence of human studies.", "criterion": "Distinguish the existence of single-ingredient arms, strata/total counts and the unverified exact category-a effects/denominators.", "basis": "E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid discarding an entire 4-arm trial as a combination trial or filling unverified single-ingredient effects with figures from the entire trial. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check comparisons by actual active ingredient and stratified analyses in factorial/4-arm trials, distinguishing single-ingredient contrasts from combination contrasts." }, { "item_id": "N32", "question_type": "Combination-product and correction boundaries", "question": "Have the FAZST combination, total motility and correction been distinguished from the direct question?", "needed": "FAZST Table3, the multiplicity footnote and original Table1 correction, and boundaries between combination/single-ingredient comparisons", "role": "Required", "role_reason": "This is needed to avoid counting different-endpoint results for combined active ingredients and a correction report as a folic-acid-only effect or an independent replication.", "application_exception": "The 95.1% CI is not changed to 95%, and zinc-related harms from the combination are not transferred to folic acid.", "criterion": "Preserve 5 mg plus zinc 30 mg, 6 months, 2370 participants, the original total-motility values and the scope of the Table1 correction.", "basis": "C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application / C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid counting different-endpoint results for combined active ingredients and a correction report as a folic-acid-only effect or an independent replication. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Separate the combination exposure and total-motility estimator from direct category-a change, linking only the columns/rows actually changed by the correction." }, { "item_id": "N33", "question_type": "Other endpoints and clinical extensions", "question": "How were pregnancy and DNA results from the same trial separated?", "needed": "FOLFIV Table6, selection/denominators of the embryo-transfer subgroup and separate DNA/live-birth outcomes", "role": "Required", "role_reason": "This is needed to avoid turning favorable pregnancy results into proof of success for sperm motility or improved live birth.", "application_exception": "The denominator of the embryo-transfer subgroup is not replaced with all 162 randomized participants. Other endpoint results are not deleted.", "criterion": "Distinguish the original values, denominators and P values for biochemical pregnancy, clinical pregnancy at 7 weeks and miscarriage from the different questions of the category-a endpoint and live birth.", "basis": "E09: M03 §3.2.4; internally defined boundaries for extending the claim / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application. Reason for applying this in this case: This is needed to avoid turning favorable pregnancy results into proof of success for sperm motility or improved live birth. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the analysis population and time of each pregnancy event against the original table, limiting extension from a semen surrogate to clinical events." }, { "item_id": "N34", "question_type": "Printing and unit conflicts in other endpoints", "question": "Have concerns about serum folate units and printed DNA values been left unresolved rather than arbitrarily corrected?", "needed": "Original tables, earlier/later versions, corrections and author explanations for serum folate units and the DNA change row", "role": "Required", "role_reason": "This is needed to avoid silently correcting candidate errors in other endpoints or importing them into category-a motility calculations.", "application_exception": "Because the currently stored summaries do not provide the exact units on both sides of the conflict or the DNA numbers, actual values are not newly invented and quoted.", "criterion": "Specify the retained candidate errors and the limitation that exact values/original locations were not provided, separating them from the main numbers.", "basis": "C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C06: M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed. Reason for applying this in this case: This is needed to avoid silently correcting candidate errors in other endpoints or importing them into category-a motility calculations. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the original table and printed units/change-row values, without arbitrary correction based only on the current general record of candidate errors." }, { "item_id": "N35", "question_type": "Funding, sponsorship and product supply", "question": "Can public funding, sponsorship and product manufacture be verified separately?", "needed": "Actual disclosures of FOLFIV funding, sponsorship, product manufacture/supply and roles/contracts", "role": "Required", "role_reason": "This is needed to avoid turning public funding and a named manufacturer into independent replication or an independent audit of all relationships.", "application_exception": "The manufacturer's name alone is not used to newly infer free product supply or detailed contracts governing involvement in the study.", "criterion": "Record PHRC 2010(10-052), AP-HP, Bailly-Creat and the limits of verification separately.", "basis": "C10: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items / C02: M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application. Reason for applying this in this case: This is needed to avoid turning public funding and a named manufacturer into independent replication or an independent audit of all relationships. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check Funding/Acknowledgments and product specifications, examining separately the roles of funding, operational sponsorship and product relationships." }, { "item_id": "N36", "question_type": "Conflicts of interest and funding of adjacent trials", "question": "Have author declarations been distinguished from limits on funding verification in other families?", "needed": "Each trial's Funding/COI, product relationships, author/institution disclosures and scope of verification", "role": "Required", "role_reason": "This is needed to avoid turning no funding/no COI declarations or unverified information into certification of independence.", "application_exception": "Relevant interests do not lead to automatic exclusion, and a declaration of no interests alone does not establish absence of bias.", "criterion": "Distinguish FOLFIV's declaration, Huang's reported absence of funding, Silva's fellowships and unverified overall funding, and the levels of information for other families.", "basis": "C10: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items / E07: M04 §4.6.1–4.6.2, M15 §15.3.1; internal application. Reason for applying this in this case: This is needed to avoid turning no funding/no COI declarations or unverified information into certification of independence. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check each family's level of disclosure and funding separately, recording shared sponsors/institutions only where links are actually verified." }, { "item_id": "N37", "question_type": "Adverse events and their collection", "question": "Have harm collection, events and denominators been verified for the same 15 mg exposure?", "needed": "AE definitions, collection and severity; person/event counts for SAEs and toxicity withdrawals; exposure/analysis denominators and duration", "role": "Required", "role_reason": "This is needed to avoid turning a tolerability-questionnaire plan into a complete tally of all AEs/SAEs and toxicity withdrawals or a count of 0 events.", "application_exception": "Efficacy results are not deleted because harm data are unverified. Spontaneous/systematic collection methods are not filled in arbitrarily either.", "criterion": "Separate the M3 questionnaire plan from unverified AE/SAE and toxicity-withdrawal person/event counts and denominators.", "basis": "E10: M19 §19.1.2–19.2.4; internal application / H01: M19 §19.1.2–19.2.4; detailed differentiation is internally designed / H04: M19 §19.1.2–19.2.4; internal application / H06: M19 §19.1.2–19.2.4, M04 §4.6.3; internal application / C07: M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed. Reason for applying this in this case: This is needed to avoid turning a tolerability-questionnaire plan into a complete tally of all AEs/SAEs and toxicity withdrawals or a count of 0 events. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check harm-collection methods for the same population/dose and person, event and follow-up denominators by arm, distinguishing reported frequency from collection limitations." }, { "item_id": "N38", "question_type": "Background on B12 and drug interactions", "question": "Have general B12/drug precautions been distinguished from trial harms?", "needed": "The partial NIH extracts and relevant B12/interaction sections of the SmPC, and medication/use contexts", "role": "Required", "role_reason": "This is needed to avoid turning warnings in general labels/summaries into events that actually occurred in FOLFIV or a magnitude of personal risk.", "application_exception": "Anticonvulsant/MTX interactions require boundaries specific to the use context, and the study dose is not an instruction for personal dosing or ART changes.", "criterion": "Separate background sources and access limitations concerning B12 masking/delayed recognition of neurological injury and interactions from trial events.", "basis": "E10: M19 §19.1.2–19.2.4; internal application / H05: M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed. Reason for applying this in this case: This is needed to avoid turning warnings in general labels/summaries into events that actually occurred in FOLFIV or a magnitude of personal risk. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the relevant warnings, jurisdiction, formulation and use context in official materials, reviewing these separately from harms observed in the trial." }, { "item_id": "N39", "question_type": "Another authorized product and regimen", "question": "Are the indications and regimen on the Flamingo 5 mg label the same as those of the 15 mg trial?", "needed": "Ingredient/route, indications, regimen and version of the Flamingo Pharma PL43461/0091 SmPC", "role": "Required", "role_reason": "This is needed to avoid using the anemia regimen of another authorized product as authorization or certification of efficacy/safety for 15 mg in male infertility.", "application_exception": "Providing the link here does not mean that the label was newly read in this task.", "criterion": "Separate the 5 mg anemia label from another manufacturer/jurisdiction from the 15 mg infertility trial.", "basis": "C05: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed / C04: M03 §3.2.1; detailed population criteria are internally designed / C03: M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed / E10: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied. Reason for applying this in this case: This is needed to avoid using the anemia regimen of another authorized product as authorization or certification of efficacy/safety for 15 mg in male infertility. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the label's actual product, jurisdiction, indications/regimen and version against the trial specifications, requiring more than a shared 5 mg designation to establish equivalence." }, { "item_id": "N40", "question_type": "Boundaries for long-term use and special populations", "question": "Does this table also adjudicate optimal dose, long-term use, vulnerable groups and personal treatment?", "needed": "Direct dose comparisons, long-term/vulnerable-population exposures and harm follow-up needed when addressing extended questions", "role": "Supplementary and extension boundaries", "role_reason": "This is needed to avoid extending the limited M3 comparison to optimal dose, long-term maintenance/safety or all populations, including children and pregnancy/lactation.", "application_exception": "Each extension is a separate question. Completion of all extension studies is not imposed as a mandatory condition for this narrow category-a change table.", "criterion": "Distinguish extensions outside the selected question by the reasons they do not apply and the separate designs they would require.", "basis": "E08: M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed / E10: M19 §19.1.2–19.2.4; internal application / H08: M19 §19.1.2–19.2.4; internal application / H09: Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied. Reason for applying this in this case: This is needed to avoid extending the limited M3 comparison to optimal dose, long-term maintenance/safety or all populations, including children and pregnancy/lactation. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "If an extension is requested, define a direct design for its population, dose, duration and endpoint, and review it separately from the original M3 question." }, { "item_id": "N41", "question_type": "Historical verdict and the role of the current table", "question": "Have the existing D/30-point verdict and document self-review been kept from being used as a new criteria-based judgment?", "needed": "The original grade/score/axes, assessment_profile, editorial_review and the scope of the current task", "role": "Required", "role_reason": "This is needed to avoid reusing a historical score, self-assessed document quality or verification wording as current clinical certification or a criteria score.", "application_exception": "The original grade/score/axes and favorable/unfavorable results are preserved unchanged as historical values. No new score or percentage of criteria met is created.", "criterion": "Separate preservation of the existing original values from statuses for individual data/recording criteria.", "basis": "C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design. Reason for applying this in this case: This is needed to avoid reusing a historical score, self-assessed document quality or verification wording as current clinical certification or a criteria score. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check the original verdict/axes and retained interpretive wording, leaving them as historical quotations without performing a new clinical reassessment." }, { "item_id": "N42", "question_type": "Boundaries for update and publication metadata", "question": "How are updates under the same ID and differing server metadata preserved?", "needed": "Original ID/URLs, revision_policy/history/triggers, and event/server-verification records for publication metadata", "role": "Required", "role_reason": "This is needed to avoid mistaking historical publication metadata in the original record for actual completed publication of the new table.", "application_exception": "The difference between publication_notes.server_deployed=false and top-level server_deployed=true is not silently overwritten.", "criterion": "Preserve original ID/URLs, revision history/triggers and metadata differences, distinguishing them from the present local stored-summary stage.", "basis": "C09: M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design / C08: M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed / C01: M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed. Reason for applying this in this case: This is needed to avoid mistaking historical publication metadata in the original record for actual completed publication of the new table. This does not constitute reading new full methodological texts, applying official RoB 2/GRADE/causality tools, or certifying minimum clinical criteria.", "condition_origin": "Internally developed criteria written individually after reading the currently retained 3110 Korean manuscript, structured evidence, actual bibliography and family definitions. This is a known development case, not a blinded or clinically preregistered exercise.", "proposed_research": "Cross-check events/times in publication metadata and link criteria revisions, material additions and actual publication to separate receipts." } ] }