LivingGLP1
Round 3 · protocol version 0.3.0

Peer review round 3

GPT-6 Astra

major revision

Read the verbatim review

Fable 5.1

minor revision

Read the verbatim review

Grok 4.7

minor revision

Read the verbatim review

Version 0.3.0 as reviewedFiles on GitHubPrevious roundNext round

Round 3: response to reviewers

Protocol version reviewed: 0.3.0. Revised version: 0.4.0.

Verdicts: GPT-6 Astra MAJOR REVISION; Fable 5.1 MINOR REVISION; Grok 4.7 MINOR REVISION. Every comment is answered below and recorded in ../comments.csv.

Summary of main changes

  • Harms: the count model is stated as a dichotomous outcome over the observation period, with incomplete follow-up judged in RoB 2 and a follow-up completeness sensitivity analysis.
  • Composite outcomes: pooling only of identical component sets and thresholds; kidney composites O22 to O22E; doubling of creatinine separate.
  • Absolute effects: reference risks only from arms whose follow-up covers the horizon; the stored horizon is uncapped and the analyzed horizon capped.
  • Nodes: iGlarLixi split by pen and switching strategy; template activation rules.
  • CINeMA: contributions always from the same evidence set; restricted sensitivity analyses rated separately.
  • Small fixes: O24C priors; recurrent event likelihood; O21 mapping; O04B relative range; O10B text; procedure and pregnancy outcomes without windows; a 4 to 12 week window for short substance use trials; administrative checklist.

GPT-6 Astra (gpt-6-astra)

C3-1 (major; Event outcomes and harms). Censored participants are treated as non-events in the count based harms model.

Response (partly revised). Agreed in part. The protocol now states that the count model analyzes a dichotomous outcome over each trial observation period (the usual analysis of adverse effects in Cochrane reviews), prefers reported time to first event estimates, extracts incomplete follow-up by arm, judges it in RoB 2 domain 3, and adds a sensitivity analysis excluding trials with more than 20 percent incomplete follow-up or a difference above 10 percentage points between arms. We did not adopt descriptive reporting whenever any participant is censored, because that would leave almost all trial evidence on harms unsynthesized.

C3-2 (major; outcomes.csv kidney composites). Kidney composites mix component sets and thresholds; doubling of creatinine is not a 50 percent decline.

Response (revised). Agreed. A general rule now pools only identical component sets and thresholds within any outcome identifier, otherwise definition strata; doubling of serum creatinine (about 57 percent) is its own outcome O22C; O22D holds composites with cardiovascular death and O22E those with albuminuria or smaller declines, both in definition strata; O50 follows O22.

C3-3 (major; Absolute effects). Median follow-up cap still extrapolates from shorter reference arms.

Response (revised). Agreed. The reference risk at the analyzed horizon comes only from reference arms whose follow-up covers it, using reported Kaplan-Meier or cumulative incidence where available; shorter arms are excluded from the baseline estimate.

C3-4 (major; nodes.csv iGlarLixi). Single pen and switching regimens pooled.

Response (revised). Agreed. Separate nodes for the 2:1 pen, the 3:1 pen and each switching strategy (permitted pens, switching threshold and titration algorithm); combined only in a sensitivity analysis.

C3-5 (major; Confidence in cumulative evidence). Contributions borrowed from a restricted analysis with different evidence.

Response (revised). Agreed. Contribution matrices represent the same trials and network as the estimate rated (for hazard scale estimates from counts, an inverse variance network of trial level log hazard ratios used only for contributions); restricted sensitivity analyses are rated separately and never substitute their rating; the lower of two framework ratings applies only to the same evidence.

C3-6 (minor; priors.csv PR04 PR08). O24C lacks priors.

Response (revised). Agreed. PR04 and PR08 apply to O24B and O24C; the text names both.

C3-7 (minor; Bayesian network meta-analysis). Negative binomial option contradicts O04B.

Response (revised). Agreed. Normal likelihood on reported log rate ratios; a count model requires a logged amendment.

C3-8 (minor; outcomes.csv O21). Obsolete expanded MACE mapping.

Response (revised). Agreed; replaced with the proposed text.

C3-9 (minor; nodes.csv OTHER_ACTIVE). Comparator template activation rule.

Response (revised). Agreed. Dose templates and the comparator template have separate activation rules in the table and the text.

Fable 5.1 (fable-5.1)

F3-1 (major; windows.csv W22). Short substance use trials (6 to 9 weeks) fall in no window.

Response (revised). Agreed. W33 (4 to 12 weeks, target 8) added as a secondary window for P14A to P14E; overlap check passed.

F3-2 (minor; priors.csv PR04 PR08). O24C priors.

Response (revised). Agreed; see C3-6.

F3-3 (minor; outcomes.csv O22C). O22C pooled 40 and 50 percent thresholds.

Response (revised). Agreed; see C3-2 (composites with cardiovascular death are now O22D in definition strata).

F3-4 (minor; Time windows; O120). O120 has no window.

Response (revised). Agreed. Per procedure and per pregnancy outcomes are stated to have no week window; O36A and O36B were removed from W00.

F3-5 (minor; O04B relative threshold). Unstated exception.

Response (revised). Agreed. O04B uses the rate ratio range 1/1.25 to 1.25 and PR14, stated in Absolute effects and in the imprecision rule.

F3-6 (minor; Time windows text). O10 versus O10B.

Response (revised). Agreed; replaced with the proposed text.

F3-7 (minor; nodes.csv OTHER_ACTIVE). Placeholder wording.

Response (revised). Agreed; see C3-9.

F2-13 follow-up (minor; Administrative checklist). Four source harvest only in the Timeline.

Response (revised). Agreed. The OpenAlex key and the reconciled four source harvest are in the administrative checklist.

Grok 4.7 (grok-4.7)

G3-1 (major; priors.csv; Effect measures). O24C priors.

Response (revised). Agreed; see C3-6.

G3-2 (minor; nodes.csv OTHER_ACTIVE). Comparator template.

Response (revised). Agreed; see C3-9.

G3-3 (minor; Time windows; W00). Procedure and pregnancy outcomes.

Response (revised). Agreed; see F3-4.

G3-4 (minor; Bayesian likelihoods). Negative binomial.

Response (revised). Agreed; see C3-7.

G3-5 (minor; O04B). Relative threshold.

Response (revised). Agreed; see F3-5.

G3-6 (minor; outcomes.csv horizons). Stored horizon versus cap.

Response (revised). Agreed. The text states that absolute_horizon_weeks is the uncapped horizon and the analyzed horizon is the smaller of it and the median reference arm follow-up.

G3-7 (minor; outcomes.csv O22C). Mixed thresholds.

Response (revised). Agreed; see C3-2.

G3-8 (minor; Time windows text). O10B label.

Response (revised). Agreed; see F3-6.

The brief every reviewer received

Peer review round 3: protocol version 0.3.0

You reviewed versions 0.1.0 (round 1) and 0.2.0 (round 2) of this protocol as reviewer {REVIEWER}. Do NOT edit, create or delete any file.

Read, in the repository root:

  • protocol/peer-review/round-2/review-{REVIEWER}.md (your round 2 review)
  • protocol/peer-review/round-2/response.md (point by point responses to all three reviewers in round 2; yours are the {PREFIX}2- items)
  • protocol/protocol.qmd (version 0.3.0) and the tables it declares authoritative: protocol/populations.csv, outcomes.csv, windows.csv, agents.csv, nodes.csv, node_classes.csv, effect_modifiers.csv, harms_nrs.csv, priors.csv, reference_sd.csv, turner_map.csv, registry_dose_candidates.csv, amendments.csv
  • search/strategies/concepts.yaml (version 1.2.0) and R/search_strategy.R

Tasks:

  1. For each of your round 2 comments, state whether the response and revision resolve it (resolved, partly resolved, not resolved), with a short reason. Where a response declines or partly adopts your proposal with a stated reason, judge the reason.
  2. List any new errors, inconsistencies or non-executable rules introduced by the revision, ordered by severity (major, then minor), with the exact file, section or row, and concrete replacement text or values.
  3. Administrative items that only the review owner can supply (team names, affiliations, funding, competing interests, confirmation of Embase access, PRESS review by a human information specialist, verification of Chinese terms by a Chinese-reading team member, confirmation and locking of provisional thresholds by clinical advisors and patient partners) are tracked as pre-registration conditions in the administrative checklist. Do not withhold acceptance for their absence alone; judge whether the methods are acceptable for registration once they are completed.

Use American English and do not use dashes as sentence punctuation. Keep under 1,500 words.

End with exactly one line: VERDICT: ACCEPT or VERDICT: MINOR REVISION or VERDICT: MAJOR REVISION ACCEPT means you would approve the methods of this protocol for registration once the administrative pre-registration conditions are completed.