Study designs for clinical trials applied to personalised medicine: a scoping review.

OBJECTIVE: Personalised medicine (PM) allows treating patients based on their individual demographic, genomic or biological characteristics for tailoring the 'right treatment for the right person at the right time'. Robust methodology is required for PM clinical trials, to correctly identify groups of participants and treatments. As an initial step for the development of new recommendations on trial designs for PM, we aimed to present an overview of the study designs that have been used in this field. DESIGN: Scoping review. METHODS: We searched (April 2020) PubMed, Embase and the Cochrane Library for all reports in English, French, German, Italian and Spanish, describing study designs for clinical trials applied to PM. Study selection and data extraction were performed in duplicate resolving disagreements by consensus or by involving a third expert reviewer. We extracted information on the characteristics of trial designs and examples of current applications of these approaches. The extracted information was used to generate a new classification of trial designs for PM. RESULTS: We identified 21 trial designs, 10 subtypes and 30 variations of trial designs applied to PM, which we classified into four core categories (namely, Master protocol, Randomise-all, Biomarker strategy and Enrichment). We found 131 clinical trials using these designs, of which the great majority were master protocols (86/131, 65.6%). Most of the trials were phase II studies (75/131, 57.2%) in the field of oncology (113/131, 86.3%). We identified 34 main features of trial designs regarding different aspects (eg, framework, control group, randomisation). The four core categories and 34 features were merged into a double-entry table to create a new classification of trial designs for PM. CONCLUSIONS: A variety of trial designs exists and is applied to PM. A new classification of trial designs is proposed to help readers to navigate the complex field of PM clinical trials.

Quality assessment practice in systematic reviews of mediation studies: results from an overview of systematic reviews.

OBJECTIVE: To describe the bias assessment practice in recently published systematic reviews of mediation studies and to evaluate the quality of different bias assessment tools for mediation analysis proposed in the literature. METHOD: We conducted an overview of systematic reviews by searching MEDLINE (OvidSP), PsycINFO (OvidSP), Cochrane Database of Systematic Reviews (OvidSP), and PubMed databases for systematic reviews of mediation studies published from 2007 to 2020. Two reviewers independently screened the title, abstracts, and full texts of the identified reports and extracted the data. The publications of all mediation-specific quality assessment tools used in these reviews were also identified for the evaluation of the tools' development and validation. RESULT: Among 103 eligible reviews, 24 (23%) reviews did not assess the risk of bias of eligible studies, and 48 (47%) assessed risk of bias using a tool that was not specifically designed to evaluate mediation analysis. 31 (30.1%) reviews assessed the risk of mediation-specific biases, either narratively or by using specific tools for mediation studies. However, none of these tools were consensus-based, rigorously developed or validated. CONCLUSION: The quality assessment practice in recently published systematic reviews of mediation studies is suboptimal. To improve the quality and consistency of risk of bias assessments for mediation studies, a consensus-based bias assessment tool is needed.

Development of ARCADIA: a tool for assessing the quality of peer-review reports in biomedical research.

OBJECTIVE: To develop a tool to assess the quality of peer-review reports in biomedical research. METHODS: We conducted an online survey intended for biomedical editors and authors. The survey aimed to (1) determine if participants endorse the proposed definition of peer-review report quality; (2) identify the most important items to include in the final version of the tool and (3) identify any missing items. Participants rated on a 5-point scale whether an item should be included in the tool and they were also invited to comment on the importance and wording of each item. Principal component analysis was performed to examine items redundancy and a general inductive approach was used for qualitative data analysis. RESULTS: A total of 446 biomedical editors and authors participated in the survey. Participants were mainly male (65.9%), middle-aged (mean=50.3, SD=13) and with PhD degrees (56.4%). The majority of participants (84%) agreed on the definition of peer-review report quality we proposed. The 20 initial items included in the survey questionnaire were generally highly rated with a mean score ranging from 3.38 (SD=1.13) to 4.60 (SD=0.69) (scale 1-5). Participants suggested 13 items that were not included in the initial list of items. A steering committee composed of five members with different expertise discussed the selection of items to include in the final version of the tool. The final checklist includes 14 items encompassed in five domains (Importance of the study, Robustness of the study methods, Interpretation and discussion of the study results, Reporting and transparency of the manuscript, Characteristics of peer reviewer's comments). CONCLUSION: Assessment of Review reports with a Checklist Available to eDItors and Authors tool could be used regularly by editors to evaluate the reviewers' work, and also as an outcome when evaluating interventions to improve the peer-review process.

The conduct and reporting of mediation analysis in recently published randomized controlled trials: results from a methodological systematic review.

OBJECTIVES: To describe the methodological characteristics of mediation analyses (MAs) reported in recent randomized controlled trials (RCTs) and to propose recommendations on the planning, conduct, and reporting of MAs in practice. STUDY DESIGN AND SETTING: We conducted a systematic review by searching MEDLINE (January 1, 2017, to December 1, 2018) for all reports of RCTs or secondary analyses of previously published RCTs that reported a MA. Two reviewers independently screened the title, abstracts, and full texts of the identified reports and extracted the data from the 98 eligible studies. RESULTS: MAs were nearly always (96%) based on a traditional mediation approach. Most studies did not report a sample size calculation for the MA (96%) or assess potential treatment-by-mediator interactions (96%). In 53% of studies, mediators and outcomes were simultaneously measured. In 57% of studies, mediator-mediator and mediator-outcome confounders were adjusted for in the analysis, although adjustment was often limited to few potential confounders. About 30% of studies discussed the assumptions underlying the MA. CONCLUSION: The conduct and reporting of MAs remained quite heterogeneous in practice. Future MAs could benefit from a consensus-based planning, conduct, and reporting guideline for MA.

Tools used to assess the quality of peer review reports: a methodological systematic review.

BACKGROUND: A strong need exists for a validated tool that clearly defines peer review report quality in biomedical research, as it will allow evaluating interventions aimed at improving the peer review process in well-performed trials. We aim to identify and describe existing tools for assessing the quality of peer review reports in biomedical research. METHODS: We conducted a methodological systematic review by searching PubMed, EMBASE (via Ovid) and The Cochrane Methodology Register (via The Cochrane Library) as well as Google® for all reports in English describing a tool for assessing the quality of a peer review report in biomedical research. Data extraction was performed in duplicate using a standardized data extraction form. We extracted information on the structure, development and validation of each tool. We also identified quality components across tools using a systematic multi-step approach and we investigated quality domain similarities among tools by performing hierarchical, complete-linkage clustering analysis. RESULTS: We identified a total number of 24 tools: 23 scales and 1 checklist. Six tools consisted of a single item and 18 had several items ranging from 4 to 26. None of the tools reported a definition of 'quality'. Only 1 tool described the scale development and 10 provided measures of validity and reliability. Five tools were used as an outcome in a randomized controlled trial (RCT). Moreover, we classified the quality components of the 18 tools with more than one item into 9 main quality domains and 11 subdomains. The tools contained from two to seven quality domains. Some domains and subdomains were considered in most tools such as the detailed/thorough (11/18) nature of reviewer's comments. Others were rarely considered, such as whether or not the reviewer made comments on the statistical methods (1/18). CONCLUSION: Several tools are available to assess the quality of peer review reports; however, the development and validation process is questionable and the concepts evaluated by these tools vary widely. The results from this study and from further investigations will inform the development of a new tool for assessing the quality of peer review reports in biomedical research.

Combining food-based dietary recommendations using Optifood with zinc-fortified water potentially improves nutrient adequacy among 4- to 6-year-old children in Kisumu West district, Kenya.

Children in developing countries often face multiple micronutrient deficiencies. Introduction of zinc-fortified water can increase zinc intake, but additional recommendations are required to address overall diet nutrient adequacy. We developed and tested food-based recommendations (FBRs) that included zinc-fortified water for children aged between 4 and 6 years from rural Kenya to achieve the best possible nutrient adequacy. Dietary intakes of 60 children aged 4-6 years, from Kisumu West district, Kenya, were assessed using a quantitative multipass 24-hr recall. Linear programming model parameters were derived, including a list of foods consumed, median serving sizes, and distribution of frequency of consumption. By using the Optifood linear programming tool, we developed FBRs for diets including zinc-fortified water. FBRs with nutrient levels achieving ≥70% recommended nutrient intake (RNI) of the World Health Organization/Food and Agriculture Organization of the United Nations RNI for most of the 12 considered nutrients were selected as the final recommendations for the children. With no FBRs and no zinc-fortified water, percent RNI coverage range was between 40% and 76% for zinc, improving to 66-101% after introduction of zinc-fortified water. The final set of FBRs achieved nutrient adequacy for all nutrients except for vitamin A (25% RNI) and folate (68% RNI). Introduction of zinc-fortified water combined with FBRs will likely improve the nutrient adequacy of diets consumed by children in Kenya but needs to be complemented with alternative interventions to ensure dietary adequacy.

Development of a prioritisation tool for the updating of clinical guideline questions: the UpPriority Tool protocol.

INTRODUCTION: Due to a continuous emergence of new evidence, clinical guidelines (CGs) require regular surveillance of evidence to maintain their trustworthiness. The updating of CGs is resource intensive and time consuming; therefore, updating may include a prioritisation process to efficiently ensure recommendations remain up to date. The objective of our project is to develop a pragmatic tool to prioritise clinical questions for updating within a CG. METHODS AND ANALYSIS: To develop the tool, we will use the results and conclusions of a systematic review of methodological research on prioritisation processes for updating and will adopt a methodological approach we have successfully implemented in a previous experience.We will perform a multistep process including (1) generation of an initial version of the tool, (2) optimisation of the tool (feasibility test of the tool, semistructured interviews, Delphi consensus survey, external review by CG methodologists and users and pilot test of the tool) and (3) approval of the final version of the tool.At each step of the process, we will (1) calculate absolute frequencies and proportions (quantitative data), (2) use content analysis to summarise and draw conclusions (qualitative data) and (3) draft a final report, discuss results and refine the previous versions of the tool. Finally, we will calculate intraclass coefficients with 95% CIs for each item and overall as indicators of agreement among reviewers. ETHICS AND DISSEMINATION: We have obtained a waiver of approval from the Clinical Research Ethics Committee at the Hospital de la Santa Creu i Sant Pau (Barcelona). The results of the study will be published in peer-reviewed journal and communicated to interested stakeholders.The tool could support the standardisation of prioritisation processes for updating CGs and therefore have important implications for a more efficient use of resources in the CG field.

Methodological systematic review identifies major limitations in prioritization processes for updating.

OBJECTIVES: The aim of the study was to identify and describe strategies to prioritize the updating of systematic reviews (SRs), health technology assessments (HTAs), or clinical guidelines (CGs). STUDY DESIGN AND SETTING: We conducted an SR of studies describing one or more methods to prioritize SRs, HTAs, or CGs for updating. We searched MEDLINE (PubMed, from 1966 to August 2016) and The Cochrane Methodology Register (The Cochrane Library, Issue 8 2016). We hand searched abstract books, reviewed reference lists, and contacted experts. Two reviewers independently screened the references and extracted data. RESULTS: We included 14 studies. Six studies were classified as descriptive (6 of 14, 42.9%) and eight as implementation studies (8 of 14, 57.1%). Six studies reported an updating strategy (6 of 14, 42.9%), six a prioritization process (6 of 14, 42.9%), and two a prioritization criterion (2 of 14, 14.2%). Eight studies focused on SRs (8 of 14, 57.1%), six studies focused on CGs (6 of 14, 42.9%), and none were about HTAs. We identified 76 prioritization criteria that can be applied when prioritizing documents for updating. The most frequently cited criteria were as follows: available evidence (19 of 76, 25.0%), clinical relevance (10 of 76; 13.2%), and users' interest (10 of 76; 13.2%). CONCLUSION: There is wide variability and suboptimal reporting of the methods used to develop and implement processes to prioritize updating of SRs, HTAs, and CGs.