IMPORTANCE: Clinicians, patients, and policy makers rely on published results from clinical trials to help make evidence-informed decisions. To critically evaluate and use trial results, readers ...require complete and transparent information regarding what was planned, done, and found. Specific and harmonized guidance as to what outcome-specific information should be reported in publications of clinical trials is needed to reduce deficient reporting practices that obscure issues with outcome selection, assessment, and analysis. OBJECTIVE: To develop harmonized, evidence- and consensus-based standards for reporting outcomes in clinical trial reports through integration with the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement. EVIDENCE REVIEW: Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT-Outcomes 2022 extension of the CONSORT 2010 statement was developed by (1) generation and evaluation of candidate outcome reporting items via consultation with experts and a scoping review of existing guidance for reporting trial outcomes (published within the 10 years prior to March 19, 2018) identified through expert solicitation, electronic database searches of MEDLINE and the Cochrane Methodology Register, gray literature searches, and reference list searches; (2) a 3-round international Delphi voting process (November 2018-February 2019) completed by 124 panelists from 22 countries to rate and identify additional items; and (3) an in-person consensus meeting (April 9-10, 2019) attended by 25 panelists to identify essential items for the reporting of outcomes in clinical trial reports. FINDINGS: The scoping review and consultation with experts identified 128 recommendations relevant to reporting outcomes in trial reports, the majority (83%) of which were not included in the CONSORT 2010 statement. All recommendations were consolidated into 64 items for Delphi voting; after the Delphi survey process, 30 items met criteria for further evaluation at the consensus meeting and possible inclusion in the CONSORT-Outcomes 2022 extension. The discussions during and after the consensus meeting yielded 17 items that elaborate on the CONSORT 2010 statement checklist items and are related to completely defining and justifying the trial outcomes, including how and when they were assessed (CONSORT 2010 statement checklist item 6a), defining and justifying the target difference between treatment groups during sample size calculations (CONSORT 2010 statement checklist item 7a), describing the statistical methods used to compare groups for the primary and secondary outcomes (CONSORT 2010 statement checklist item 12a), and describing the prespecified analyses and any outcome analyses not prespecified (CONSORT 2010 statement checklist item 18). CONCLUSIONS AND RELEVANCE: This CONSORT-Outcomes 2022 extension of the CONSORT 2010 statement provides 17 outcome-specific items that should be addressed in all published clinical trial reports and may help increase trial utility, replicability, and transparency and may minimize the risk of selective nonreporting of trial results.
The Core Outcome Set-STAndards for Development (COS-STAD), published in 2017, contains 11 standards (12 criteria) describing minimum design criteria for core outcome set (COS) development. We aimed ...to identify and appraise all pediatric COS published prior to COS-STAD, and assess methods of child and family involvement in their development.
This methodological review included documents that described the development of pediatric COS up to and including 2017. Reviewers independently assessed each COS against COS-STAD criteria, and methods of involvement were synthesized.
A total of 56 pediatric COS were identified, meeting a median of five COS-STAD criteria. Nearly all met criteria on COS scope specification for setting, health condition, and population; 41% met criteria for intervention. Standards were more often met for the involvement of researchers/health professionals (64%) than for patients or their representatives (29%). Few met standards for achieving COS consensus (4–23%). Methods of child and family engagement varied and were limited.
A large proportion of pediatric COS developed prior to COS-STAD recommendations show gaps in design methodology. Updated and newly developed pediatric COS would benefit from the inclusion of the child and family voice, implementing a priori criteria for COS consensus, and clear reporting.
Recently a standard set for overall pediatric health outcomes in routine care was developed, which includes patient (or proxy) reported outcome measures (PROMs) for global health, cognitive ...functioning, and self-efficacy.
To determine whether the following PROMs have sufficient measurement properties to be used in pediatric routine care: PROMIS Pediatric and Parent Proxy Scale - Global Health 7+2, PROMIS Parent Proxy Short Form - Cognitive Function 7a, and NIH Toolbox Self-Efficacy CAT Ages 13 to 17.
Embase, Psych INFO, and Web of Science were searched from year of inception of each PROM to May 25, 2020; Medline to October 24, 2022.
English, full-text peer-reviewed articles that evaluated measurement properties of included PROMs were eligible.
The COSMIN guideline for systematic reviews was used to appraise eligible studies and synthesize the overall evidence.
Screening >4000 titles yielded 4 to 6 eligible empirical studies for each PROM. The PROMIS instruments had sufficient content validity with low-quality evidence and at least low-quality evidence for sufficient structural validity and internal consistency. The NIH Toolbox lacked essential evidence for content validity.
Assessments of measurement properties were based on information reported in the included studies; underreporting might have led to less favorable ratings.
The PROMIS instruments assessed in this review measure their intended construct for their targeted age group; clinicians can use these PROMs in pediatric routine care. Additional studies evaluating measurement properties, including content validity, are needed for the NIH Toolbox before it should be recommended for use in clinical practice.
Clinicians, patients, and policy-makers rely on published evidence from clinical trials to help inform decision-making. A lack of complete and transparent reporting of the investigated trial outcomes ...limits reproducibility of results and knowledge synthesis efforts, and contributes to outcome switching and other reporting biases. Outcome-specific extensions for the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT-Outcomes) and Consolidated Standards of Reporting Trials (CONSORT-Outcomes) reporting guidelines are under development to facilitate harmonized reporting of outcomes in trial protocols and reports. The aim of this review was to identify and synthesize existing guidance for trial outcome reporting to inform extension development.
We searched for documents published in the last 10 years that provided guidance on trial outcome reporting using: an electronic bibliographic database search (MEDLINE and the Cochrane Methodology Register); a grey literature search; and solicitation of colleagues using a snowballing approach. Two reviewers completed title and abstract screening, full-text screening, and data charting after training. Extracted trial outcome reporting guidance was compared with candidate reporting items to support, refute, or refine the items and to assess the need for the development of additional items.
In total, 1758 trial outcome reporting recommendations were identified within 244 eligible documents. The majority of documents were published by academic journals (72%). Comparison of each recommendation with the initial list of 70 candidate items led to the development of an additional 62 items, producing 132 candidate items. The items encompassed outcome selection, definition, measurement, analysis, interpretation, and reporting of modifications between trial documents. The total number of documents supporting each candidate item ranged widely (median 5, range 0-84 documents per item), illustrating heterogeneity in the recommendations currently available for outcome reporting across a large and diverse sample of sources.
Outcome reporting guidance for clinical trial protocols and reports lacks consistency and is spread across a large number of sources that may be challenging to access and implement in practice. Evidence and consensus-based guidance, currently in development (SPIRIT-Outcomes and CONSORT-Outcomes), may help authors adequately describe trial outcomes in protocols and reports transparently and completely to help reduce avoidable research waste.
IMPORTANCE: Complete information in a trial protocol regarding study outcomes is crucial for obtaining regulatory approvals, ensuring standardized trial conduct, reducing research waste, and ...providing transparency of methods to facilitate trial replication, critical appraisal, accurate reporting and interpretation of trial results, and knowledge synthesis. However, recommendations on what outcome-specific information should be included are diverse and inconsistent. To improve reporting practices promoting transparent and reproducible outcome selection, assessment, and analysis, a need for specific and harmonized guidance as to what outcome-specific information should be addressed in clinical trial protocols exists. OBJECTIVE: To develop harmonized, evidence- and consensus-based standards for describing outcomes in clinical trial protocols through integration with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement. EVIDENCE REVIEW: Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the SPIRIT-Outcomes 2022 extension of the SPIRIT 2013 statement was developed by (1) generation and evaluation of candidate outcome reporting items via consultation with experts and a scoping review of existing guidance for reporting trial outcomes (published within the 10 years prior to March 19, 2018) identified through expert solicitation, electronic database searches of MEDLINE and the Cochrane Methodology Register, gray literature searches, and reference list searches; (2) a 3-round international Delphi voting process (November 2018-February 2019) completed by 124 panelists from 22 countries to rate and identify additional items; and (3) an in-person consensus meeting (April 9-10, 2019) attended by 25 panelists to identify essential items for outcome-specific reporting to be addressed in clinical trial protocols. FINDINGS: The scoping review and consultation with experts identified 108 recommendations relevant to outcome-specific reporting to be addressed in trial protocols, the majority (72%) of which were not included in the SPIRIT 2013 statement. All recommendations were consolidated into 56 items for Delphi voting; after the Delphi survey process, 19 items met criteria for further evaluation at the consensus meeting and possible inclusion in the SPIRIT-Outcomes 2022 extension. The discussions during and after the consensus meeting yielded 9 items that elaborate on the SPIRIT 2013 statement checklist items and are related to completely defining and justifying the choice of primary, secondary, and other outcomes (SPIRIT 2013 statement checklist item 12) prospectively in the trial protocol, defining and justifying the target difference between treatment groups for the primary outcome used in the sample size calculations (SPIRIT 2013 statement checklist item 14), describing the responsiveness of the study instruments used to assess the outcome and providing details on the outcome assessors (SPIRIT 2013 statement checklist item 18a), and describing any planned methods to account for multiplicity relating to the analyses or interpretation of the results (SPIRIT 2013 statement checklist item 20a). CONCLUSIONS AND RELEVANCE: This SPIRIT-Outcomes 2022 extension of the SPIRIT 2013 statement provides 9 outcome-specific items that should be addressed in all trial protocols and may help increase trial utility, replicability, and transparency and may minimize the risk of selective nonreporting of trial results.
There is a fundamental link between cholinergic neurotransmitter function and overt and covert actions. Major cholinergic systems include peripheral motor neurons organizing skeletal muscle movements ...into overt behaviors and cholinergic neurons in the basal forebrain and mesopontine regions that mediate covert actions realized as states of consciousness, arousal, selective attention, perception, and memory. Cholinergic interneurons in the striatum appear to integrate conscious and unconscious actions. Neural network models involving cholinergic neurons, as well as neurons using other neurotransmitters, emphasize connective circuitry as being responsible for both motor programs and neural correlates of higher consciousness. This, however, is only a partial description. At a more fundamental level lie intracellular mechanisms involving the cytoskeleton, which are common to both muscle contraction and neuroplastic responses in targets of central cholinergic cells attendant with higher cognition. Acetylcholine, acting through nicotinic receptors, triggers interactions between cytoskeletal proteins in skeletal muscle cells, as has been long known. There is also evidence that acetylcholine released at central sites acts through muscarinic and nicotinic receptors to initiate responses in actin and microtubule proteins. These effects and their implications for cholinergic involvement in higher cognition are explored in this review.
22q11.2 deletion syndrome (22q11.2DS) is the most common micro-deletion syndrome. The associated 22q11.2 deletion conveys the strongest known molecular risk for schizophrenia. Neurodevelopmental ...phenotypes, including intellectual disability, are also prominent though variable in severity. Other developmental features include congenital cardiac and craniofacial anomalies. Whereas existing mouse models have been helpful in determining the role of some genes overlapped by the hemizygous 22q11.2 deletion in phenotypic expression, much remains unknown. Simple model organisms remain largely unexploited in exploring these genotype-phenotype relationships.
We first developed a comprehensive map of the human 22q11.2 deletion region, delineating gene content, and brain expression. To identify putative orthologs, standard methods were used to interrogate the proteomes of the zebrafish (D. rerio), fruit fly (D. melanogaster), and worm (C. elegans), in addition to the mouse. Spatial locations of conserved homologues were mapped to examine syntenic relationships. We systematically cataloged available knockout and knockdown models of all conserved genes across these organisms, including a comprehensive review of associated phenotypes.
There are 90 genes overlapped by the typical 2.5 Mb deletion 22q11.2 region. Of the 46 protein-coding genes, 41 (89.1 %) have documented expression in the human brain. Identified homologues in the zebrafish (n = 37, 80.4 %) were comparable to those in the mouse (n = 40, 86.9 %) and included some conserved gene cluster structures. There were 22 (47.8 %) putative homologues in the fruit fly and 17 (37.0 %) in the worm involving multiple chromosomes. Individual gene knockdown mutants were available for the simple model organisms, but not for mouse. Although phenotypic data were relatively limited for knockout and knockdown models of the 17 genes conserved across all species, there was some evidence for roles in neurodevelopmental phenotypes, including four of the six mitochondrial genes in the 22q11.2 deletion region.
Simple model organisms represent a powerful but underutilized means of investigating the molecular mechanisms underlying the elevated risk for neurodevelopmental disorders in 22q11.2DS. This comparative multi-species study provides novel resources and support for the potential utility of non-mouse models in expression studies and high-throughput drug screening. The approach has implications for other recurrent copy number variations associated with neurodevelopmental phenotypes.
Results of randomized controlled trials (RCTs) and, ideally, the synthesis of RCT results into meta-analyses, drive both clinical and policy decision making about health care interventions and inform ...new avenues for research. Selection of the right health outcomes to measure, analyze, and report on when designing a trial therefore is key in ensuring that the research will be useful and will have maximum impact.
As in many areas of medicine, wide variability exists in pediatric mental health research as to which outcomes are selected, how they are measured, and how they are reported. Variability in outcome selection and measurement may stem from various factors, including a tendency to select what is feasible or historical to measure rather than a focus on what is important to measure and how best to measure it. The resulting variability limits comparing and combining the results from different trials addressing a similar question in meta-analyses, hindering the translation of research to practice.
The objective of this article is to highlight the importance of outcome selection, measurement, and reporting in the translation of research to clinical practice.
Evidence-based mental health care for children and youth critically depends on properly conducted randomized controlled trials (RCTs) and prospective studies that investigate change in mental health ...outcomes over time. As evidence accumulates, it can be synthesized through systematic reviews and meta-analyses that combine the results of many studies into a single estimate of effect. Clinical practice guidelines incorporate this information along with input from stakeholders and content experts, who fill in evidence gaps to formulate recommendations for best practice. Collectively, this evidence generation and synthesis process, once implemented, supports better long-term outcomes for the population by highlighting the "best available evidence" and reducing variability in clinical care. In addition, this process identifies knowledge gaps that might inform the field's research agenda. The objective of this commentary is to examine the potential of developing and implementing "Core Outcome Sets" (COS) as a means of reducing variability in the measurement and reporting of outcomes across RCTs and cohort studies, and thereby promoting the translation of evidence to practice.
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