Draft synthesis: incretin receptor agonists in adolescents — submissions
The 16 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
16 submissions were received. Each is published in full below with its declared interest, the secretariat response and the disposition. The Institute publishes submissions it did not accept in the same form as those it did.
Quantitative claims are reproduced without the method that produced them
Several figures in the draft are quoted from sources that determined them by different methods. A figure obtained by one determination and a figure obtained by another are not comparable, and the draft places them in the same sentence without distinguishing them.
The respondent, an analytical chemist, proposes that every quantitative claim carry the method that produced it at the point of use rather than in the reference.
The secretariat accepts this submission. Placing two figures side by side is an implicit claim that they are the same kind of quantity, and in the cases identified they were not.
Every quantitative claim now carries the determination that produced it at the point of use, and figures obtained by non-comparable methods are no longer presented in the same row or sentence.
A sortable table implies a comparison the underlying data do not support
The draft presents a sortable table whose columns are drawn from sources of differing quality. The respondent states that sorting on such a column produces an ordering that looks like a ranking and is not one.
The respondent proposes that sorting be disabled on any column whose values are not commensurable.
The secretariat notes this submission and records that the point is correct in principle.
No amendment arises here because every sortable table in the document set already carries a standing statement above it that the ordering is not a ranking and that the values in each column are commensurable only where the column header says so. The proposal to disable sorting was considered and not adopted, because a reader who cannot sort a table generally sorts it elsewhere and without the statement.
Point estimates are given without an interval
Several estimates in the draft appear as single figures. The respondent states that a point estimate without an interval invites a precision the underlying data do not support, and that the effect is worst where the estimate is drawn from a small contributing set.
The respondent proposes that no point estimate appear anywhere in the document set without its interval, including in summary tables and in the abstract.
The secretariat accepts this submission in part. Intervals are added wherever the source reports one. The proposal is declined for figures the source published without an interval, because the Institute will not compute an interval a source did not report.
Every estimate now carries its interval where the source reported one, and where it did not, the estimate is annotated as reported without an interval rather than left to appear as a precise figure.
Two included studies do not meet the registered eligibility criteria
The respondent identifies two studies in the included set whose duration falls below the minimum stated in the protocol, and one excluded study that appears to meet every criterion.
The respondent proposes that the three be reassessed and that the outcome of the reassessment be recorded whichever way it goes.
The secretariat accepts this submission in part. On reassessment, one of the two included studies does fall below the minimum duration and has been removed. The second reports a duration that met the criterion in the protocol version registered at the time. The excluded study was excluded for a reason not clearly recorded, which was a documentation failure.
One study has been removed from the included set and the estimate recomputed, the exclusion reason for the third study has been corrected in the excluded-studies table, and the screening decisions are now recorded against the protocol version in force at the time of screening.
Declared interests should appear on the document rather than on a separate page
The draft links to a central conflicts register. The respondent argues that a reader assessing whether to rely on a particular document should not have to leave it to find out who assessed it and what they declared.
The respondent proposes that the interests of every named contributor to a document be printed on that document.
The secretariat notes this submission and records that the draft already provides for it, which the respondent could reasonably have missed because the provision sits in an appendix.
Every document carries the declared interests of its named contributors in its front matter, and the central register exists so that a reader can see a person across all documents rather than one at a time. No amendment arises; the provision has been moved from the appendix into the body of the methodology document so that it is findable.
The same concept is given three different names in one document
The draft refers to the same quantity as a response rate, a responder proportion and a categorical outcome in different sections. The respondent, who works in health-technology assessment, states that a reader cannot tell whether the three refer to one thing or to three.
The respondent proposes that the glossary term be used at every occurrence and that the glossary entry be linked at first use in each section rather than only at first use in the document.
The secretariat accepts this submission. The variation was stylistic and its cost to the reader exceeds any benefit.
A single term is now used throughout for each defined concept, and the glossary entry is linked at first use within each section rather than once per document.
Intention-to-treat and efficacy-estimand results are combined without distinction
Several contributing trials report both a treatment-policy result and an efficacy result that censors at discontinuation. The draft draws from whichever is reported first in each paper.
The respondent, a trial statistician, states that the two answer different questions, that the difference is substantial where discontinuation is common, and that a synthesis should choose one and say which.
The secretariat accepts this submission. Mixing estimands within a single pooled estimate is a defect of the synthesis rather than of the trials.
The treatment-policy estimand is used throughout as the primary analysis, the efficacy estimand is reported as a secondary analysis where available, and the estimand used is stated in every row of the summary of findings.
Absence of evidence is presented in a form a reader will take as negative evidence
Where the Institute has identified no study, the draft states that no evidence was found. In several places that sentence sits immediately after a paragraph describing an adverse outcome, and the juxtaposition invites the reading that the compound was studied and found wanting.
The respondent proposes a standing formulation, used identically wherever the situation arises, distinguishing an outcome that was studied and not demonstrated from an outcome that has not been studied at all.
The secretariat accepts this submission. The two states are different, they support different decisions, and the draft rendered them in language a reader could not reliably separate.
A standing formulation has been adopted and is applied wherever an evidence gap is recorded, distinguishing an outcome assessed and not demonstrated from an outcome not assessed. The formulation is identical at every occurrence so that it can be recognised at a glance.
A single-trial result is presented in the visual form of a pooled estimate
An outcome contributed by one trial is presented in the same forest plot format as outcomes contributed by several. The respondent states that the format carries an implication of replication that a single trial does not have.
The respondent proposes that single-trial outcomes be presented differently and labelled as unreplicated.
The secretariat accepts this submission. The form of a graphic is part of what it asserts.
Outcomes contributed by a single trial are now reported without a pooled diamond, labelled as unreplicated, and downgraded for imprecision or inconsistency according to the framework rather than presented as a synthesis.
Doses differing several-fold are pooled without examining dose-response
Contributing trials administer doses that differ by a factor of several. The draft pools them and reports one estimate. The respondent states that where a dose-response relationship exists the pooled figure corresponds to no dose that anyone receives.
The respondent proposes that estimates be reported by dose and that dose-response be examined where the data allow.
The secretariat accepts this submission. A pooled estimate across doses is an estimate for an average dose that no protocol specifies.
Estimates are now reported by dose group, a dose-response examination is reported where three or more dose levels contribute, and the pooled across-dose estimate is removed rather than retained alongside.
The choice of effect measure is not justified and changes the appearance of the result
The draft reports relative effects for benefits and absolute effects for harms. The respondent states that the combination flatters the intervention and that the choice should be justified or made uniform.
The respondent proposes that both relative and absolute effects be reported for every outcome.
The secretariat accepts this submission in part. Both measures are reported for every outcome where the baseline risk needed for the absolute effect can be stated. Where it cannot, the relative effect is reported alone with the reason.
Every outcome now reports the relative effect and, where an assumed baseline risk can be stated and sourced, the corresponding absolute effect, with the baseline risk and its source given in the same row.
Registered trials that never reported are not counted anywhere in the review
The respondent states that the screening flow accounts for records retrieved and excluded but does not record registered trials identified with no posted result, which are neither included nor excluded and simply disappear.
The respondent proposes that they be counted and reported as a category, with the proportion of the registered evidence base they represent.
The secretariat accepts this submission. A review that cannot say how much of the evidence base is unreported cannot say how much weight its own estimate deserves.
Registered trials without posted results are now identified, counted and reported as a distinct category in the screening flow, with the proportion of registered participants they represent stated in the limitations.
The conclusion is stated more strongly than the certainty rating supports
The draft rates the anchor outcome at low certainty and then states in the conclusion that the intervention is effective. The respondent states that the two sentences cannot both be true as written.
The respondent proposes that conclusion language be tied mechanically to the certainty rating, so that a low rating cannot produce an unqualified claim.
The secretariat accepts this submission. The mismatch is the failure mode the certainty framework exists to prevent.
Conclusion wording is now drawn from a fixed set of formulations tied to the certainty rating, so that a low certainty rating produces a statement that the evidence may suggest an effect and that the estimate is likely to change with further research.
The review question is drawn too broadly to be answerable
The respondent states that the population as registered spans groups in which the intervention would be expected to behave differently, and that a single estimate across them is uninformative.
The respondent proposes that the question be split and the review re-registered.
The secretariat does not accept this submission. The breadth was registered before screening, the pre-specified subgroups address the variation the respondent identifies, and re-registering after the results are known would convert a pre-specified analysis into a post hoc one.
The question stands as registered. The point is recorded in the limitations, and the assessment committee has noted it for the protocol of the next version of this review, which will be registered before the search is run. The submission remains published in full.
Efficacy outcomes are rated for certainty and harms are not
The draft assigns certainty ratings to the efficacy outcomes and reports harms narratively without ratings. The respondent states that the asymmetry implies harms are less amenable to assessment when they are simply less well measured.
The respondent proposes that harms carry certainty ratings on the same scale, with the reasons for downgrading stated.
The secretariat accepts this submission. Rating one side of the balance and not the other produces a document that cannot be used to weigh them.
Every reported harm now carries a certainty rating on the same scale as the efficacy outcomes, with the downgrade reasons stated, and discontinuation for adverse events appears in the summary of findings rather than in an annex.
The document should state what a reader ought to do
The draft assesses evidence and stops. The respondent, a practising clinician, states that a reader arriving at the document with a decision to make is left to convert an assessment into an action without help, and proposes that each document close with a recommendation.
The respondent argues that other evidence bodies issue recommendations and that declining to do so transfers the difficult part of the work to the reader.
The secretariat does not accept this submission, and records that the point is a reasonable one rather than a misunderstanding.
The Institute assesses evidence and does not issue recommendations, because a recommendation embeds values and a resource context that the Institute does not hold and cannot state. That constitutional limit is published on the methodology page and is not varied by consultation. The submission remains published in full.
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- International Organization for Standardization. ISO/IEC 17025:2017 General Requirements for the Competence of Testing and Calibration Laboratories. ISO/IEC Standard 2017;3rd edition. identifier not held by the Institute
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.