Journal of Clinical Epidemiology最新文献

Background: Health equity aims to provide all individuals with equal and fair opportunities to achieve optimal health. Practice guidelines can play a pivotal role in advancing health equity, yet, few organizations utilize tools to systematically integrate health equity considerations. Thus, it is important to establish a foundation for practical tools to support the systematic integration of health equity considerations. This manuscript proposes principles for the integration of health equity considerations in the practice guideline enterprise.

Methods: In the process of developing an equity extension for the GIN-McMaster guideline development checklist, we established a diverse advisory group of guideline developers, patients, members of the public experiencing inequities, health equity researchers and guideline developers. We formulated the principles informed by a methodological review of guideline handbooks, and iterative discussions between working group members.

Results: We identified seven principles for considering integrating health equity considerations in the practice guideline enterprise. 1) Articulating health equity, 2) a priori planning for considering health equity, 3) Selection and engagement with individuals with lived experiences of inequities, 4) Equity in evidence synthesis, 5) Developing equity-informed recommendations, 6) Inclusive knowledge mobilization, and 7) Evaluating the impact of health equity considerations. We elaborated on the importance of the principles using published examples and mapped them to the different phases of the guideline development process.

Conclusions: Guideline developers should adhere to these principles in the development of guidelines and health equity guideline development and appraisal tools. These principles are the foundational concepts for developing health equity extension items for the GIN-McMaster guideline development checklist.

Objectives: If randomised controlled trials can be successfully emulated using real-world data (RWD), confidence in the validity of RWD for estimating treatment effects for questions that have not been assessed in trials increases. We used routinely collected administrative and clinical national linked datasets from England to emulate the PR07 trial for high-risk prostate cancer patients, which compared the effects of radiotherapy added to hormone therapy (RT+HT) within 8 weeks of randomisation (the 'grace period') and hormone therapy only (HT) on all-cause mortality. We highlight methodological choices required and challenges encountered in emulating this trial.

Study design and setting: Patients diagnosed with prostate cancer from 2014 to 2020 were identified from the routine national linked datasets. Diagnosis was taken as the time zero. As few patients initiated radiotherapy within 8 weeks of diagnosis, we considered target trials with grace periods of 4-6 months. Estimands of interest were hazard ratios (HRs) and survival probabilities over 7 years. The cloning-censoring-and-weighting (CCW) approach was used to control for measured confounding and to allow for the grace period. We also used an extension (the 'landmark-CCW' approach), in which we consider several time-origins post-diagnosis, enabling us to use a grace period of 8 weeks as in PR07.

Results: A total of 2,690 patients were eligible for inclusion in the emulated trial. The CCW analysis using a grace period of 6 months gave an estimated HR of 0.48 (95%CI: 0.34-0.60) and 7-year survival estimates of 80.7% (95%CI: 74.3-87.0) for the RT+HT strategy and 65.6% (95%CI: 62.8, 68.1) for HT only strategy, and corresponding risk difference of 15.1% (95%CI: 11.5-18.9). The corresponding HR from the landmark-CCW approach was 0.58 (95%CI: 0.51-0.65) and with survival estimates of 80.7% (95%CI: 77.7-83.8) for RT+HT strategy and 69.8% (95%CI: 68.2-71.4) for the HT only strategy, and a risk difference of 10.9% (95%CI: 6.3-15.9).

Conclusions: Our findings from the emulated trial using RWD are broadly consistent with those from PR07, with RT+HT estimated to result in better survival compared to HT only. However, the findings were not replicated exactly, with PR07 reporting a HR of 0.77 (95%CI: 0.61-0.98) over 7 years of follow-up. Differences may be in part due to challenges in defining time zero and allowing for a treatment grace period of the same duration as in PR07. Our study considered ways in which these challenges can be addressed, and our findings affirm the utility of RWD for estimating treatment effects.

Objectives: We aimed to assess how often randomized controlled trials (RCTs) in adult cardiac surgery found significant mortality benefits for newer interventions versus older ones, whether observed treatment effect estimates changed over time and whether RCTs and non-randomized observational studies gave similar results.

Methods: We searched journals likely to publish systematic reviews on adult cardiac surgery for meta-analyses of mortality outcomes and that included at least one RCT, with or without observational studies. Relative treatment effect sizes were evaluated overall, over time, and per study design.

Results: A total of 73 meta-analysis comparisons (824 study outcomes on mortality, 519 from RCTs, 305 from observational studies) were eligible. The median mortality effect size was 1.00, IQR 0.54-1.30 (1.00 among RCTs, 0.91 among observational studies, p=0.039). Four RCTs and 6 observational studies reached p<0.005 favoring newer interventions. Two meta-analyses reached p<0.005 favoring newer interventions. Effect size for experimental interventions relative to controls did not change over time overall (p=0.64) or for RCTs (p=0.30), and there was a trend for increase in observational studies (p=0.027). In 34 meta-analyses with both RCTs (n=95) and observational studies (n=305), the median relative summary effect (summary effect in observational studies divided by summary effect in RCTs) was 0.87 (IQR, 0.55-1.29); meta-analysis of the relative summary effects yielded a summary of 0.93 (95% CI, 0.74-1.18).

Conclusions: The vast majority of newer interventions had no mortality differences over older ones both overall and specifically in RCTs, while benefits for newer interventions were reported more frequently in observational studies.

Objective: Recommendations about the comparison of multiple interventions should ideally be based on direct evidence. Issues may arise in a guideline development group (GDG) if the intervention of interest is compared with an alternative, widely accepted intervention, and direct evidence suggests that the former may be at least as effective as the latter .

Study design and setting: In this report we present our experience during the development of evidence-based recommendations, according to the GRADE methodology, on azathioprine as an off-label treatment for multiple sclerosis in settings with limited resources.

Results: Direct evidence from small studies on critical outcomes (relapse and worsening of disability) probably favored, with very low certainty, azathioprine over interferon, a widely accepted labelled treatment for multiple sclerosis. Indirect evidence on interferon compared to placebo, despite being supported by larger trials, favored interferon with very low certainty. These observations were surprising for some GDG members and challenged their confidence in the seemingly established health effects of interferon and on how they should comparatively evaluate azathioprine. De facto, the long-established treatment, that before the availability of newer disease-modifying treatments had been considered for years as a standard of care, was only based on very low certainty evidence, which was paired by very low certainty evidence in favor of another treatment. To not deviate from the mandate and scope of the guideline, through discussion and voting, conditional recommendations supporting the use of azathioprine were made where interferon and/or other treatments were not available and affordable. Although the GDG concluded that there was insufficient evidence to recommend azathioprine ahead of interferon, some of its members would have preferred to rank azathioprine ahead of interferon, based on the published evidence. An alternative solution may have been to add a new question and rediscuss the role of the established treatment, i.e. interferon.

Conclusion: Recommendations should be developed according to the target recommendation question and the scope of the guideline. Scenarios that question the perceived health effects of long-established interventions must be met by an openness to reconsider such standards of care. If directed by the GDG, external, indirect evidence on the widely accepted intervention may have to be assessed and this should be considered when planning a guideline recommendation. Potential alternative approaches on how to formulate the final recommendation should be carefully weighted in relation to the context and setting to which recommendations are targeted.

Objective: As multiple sophisticated techniques are used to evaluate psychometric scales, in theory reducing error and enhancing measurement of patient reported outcomes, we aimed to determine whether applying different psychometric analyses would demonstrate important differences in treatment effects.

Study design and setting: We conducted secondary analysis of individual participant data from 20 antidepressant treatment trials obtained from Vivli.org (n=6,843). Pooled item-level data from the HRSD-17 were analysed using confirmatory factory analysis (CFA), item response theory (IRT) and network analysis (NA). Multilevel models were used to analyse differences in trial effects at approximately 8 weeks (range 4-12 weeks) post-treatment commencement, with standardised mean differences calculated as Cohen's d. Effect size outcomes for the original total depression scores were compared with psychometrically-informed outcomes based on abbreviated and weighted depression scores.

Results: Several items performing poorly during psychometric analyses and were eliminated, resulting in different models being obtained for each approach. Treatment effects were modified as follows per psychometric approach: 10.4%-14.9% increase for CFA, 0%-2.9% increase for IRT, 14.9%-16.4% reduction for NA.

Conclusion: Psychometric analyses differentially moderate effect size outcomes depending on the method used. In a 20-trial sample, factor analytic approaches increased treatment effect sizes relative to the original outcomes, NA decreased them, and IRT results reflected original trial outcomes.

Objectives: This study aimed to explore research trends and areas of interest in systematic reviews (SRs) and meta-analyses of clinical prediction models (CPMs), while summarizing their conduct and reporting characteristics.

Study design and setting: A scoping review was conducted, with searches performed in PubMed, Embase, and the Cochrane Library from inception to January 7, 2023. Pairs of reviewers independently screened potentially eligible studies. Data on bibliographic and methodological characteristics were collected and analyzed descriptively.

Results: A total of 1,004 SRs published between 2001 and 2023 were included. The number of SRs increased significantly after 2020, with the majority originating from Europe (46.7%) and Asia (24.1%). Populations and outcomes were categorized into 19 and 34 classifications, respectively. The general population was the most frequently targeted (38.7%), and mortality was the most common outcome (18.9%). The prediction or diagnosis of neoplasms in the general population was the most prevalent focus (7.2%). Prognostic models were included only in 69.6% of SRs, while diagnostic models were included in 16.8%; 13.6% included both. The number of primary studies included in SRs ranged from 1 to 495, and the models ranged from 1 to 731. Most SRs lacked standardized reporting: 88.3% did not frame their review questions using established frameworks, and 79.8% did not follow standardized checklists for data extraction. Quality and risk of bias assessments were reported in 76.5% of SRs, with the PROBAST (27.9%) and QUADAS-2 (17.0%) tools being the most common. Narrative synthesis was the predominant method for evidence summarization (63.5%), while meta-analysis was conducted in 36.5%. Measures of model performance were summarized in 80.5% of SRs, with discrimination being the most frequently reported (67.7%). Only 5.2% assessed the certainty of evidence. Moreover, 42.2% of SRs published a protocol, 76.0% clearly stated support and 91.1% stated competing interests.

Conclusion: The number of SRs on CPMs has grown substantially, with increasing diversity in populations and outcomes. However, significant variability in conduct and reporting was observed. Future SRs should strictly follow well-developed guidelines, and a dedicated study assessing the reporting quality and risk of bias in SRs of CPMs is warranted.

Objective: The prioritization of clinical practice guideline (CPG) efforts is particularly challenging for rare genetic neurodevelopmental disorders given the large number of (ultra)rare conditions and limited resources. We aimed to establish criteria for the priority-setting of CPG topics within the European Reference Network (ERN) ITHACA (Intellectual disability, TeleHealth, Autism and Congenital Anomalies) based on stakeholder input.

Study design and setting: Sets of priority-setting criteria for aetiology-specific CPGs and shared health topic CPGs (across aetiologies) were generated using a two-phase consensus process. The first phase consisted of initial criteria generation, internal feedback from the ERN-ITHACA Executive Committee and Patient Advisory Board, and stakeholder input through an open survey. The second phase consisted of a two-round modified Delphi and consensus meeting with an expert panel consisting of patient advocates, clinicians, and methodologists.

Results: The final sets of priority-setting criteria included absence of existing guidance, high burden for affected individuals and families, and specific health risks requiring adaptation from usual care. Additionally, complexity and treatment availability were included for aetiology-specific CPGs and common occurrence and societal burden were included for CPGs for shared health topics. Availability and interest of clinical experts and patient organizations were considered required to produce CPGs; shared health topics addressed through dedicated CPGs need to be universal across aetiologies.

Conclusion: Aligning with stakeholder perspectives in priority-setting is required to allocate scarce resources to the development of high-priority CPGs for rare conditions. Priority-setting criteria specific to the rare condition context were identified. CPG development was considered a particular priority important for complex conditions and/or healthcare and where care is non-standard. Practice variation was not selected as a priority-setting criterion.

Objectives: To identify, summarise, and analyse published comments relevant to the PRISMA-P (Preferred Items for Reporting Systematic reviews and Meta-Analyses Protocols) 2015 reporting guideline for systematic review protocols, with special emphasis on suggestions for guideline modifications.

Methods: We included documents (e.g., empirical studies and social media posts) that included comments relevant to PRISMA-P 2015. We searched bibliographic databases (e.g., Embase, MEDLINE, Scopus, from January 1^st 2015 to February 2^nd 2024) and other sources (e.g., BMJ rapid responses, BMC Blog Network, from January 1^st 2015 to April 22^nd 2024). Two authors independently assessed documents for inclusion, extracted data, and categorised comments. We categorised comments as 'suggestion for modification to the wording of an existing PRISMA-P 2015 item', 'suggestion for a new item', 'suggestion for deletion of an existing PRISMA-P 2015 item', or 'additional comment'. We categorised each comment into themes and provided a summary and examples of the proposed suggestions. We analysed the characteristics of the suggestions by describing the rationale and comparing with existing PRISMA-P 2015 guidance.

Results: We assessed full text of 1,912 potentially eligible documents and included 28 documents with 38 comments. Eleven comments suggested modifications to existing guideline items. Multiple comments proposed modifications to items related to eligibility criteria (three comments made different suggestions, e.g., one comment suggested to include reporting guidance relating to retracted papers) and data synthesis (three comments made different suggestions, e.g., one comment suggested to add reporting guidance relating to prediction intervals for random-effects meta-analyses). There were 11 comments suggesting new items. The data items section of PRISMA-P 2015 received the most comments (five comments made different suggestions, e.g., three comments suggested to add content on pre-specifying whether authors plan to extract information on funding and conflicts of interest among the included studies). None of the included comments suggested to delete items or content. Most of the suggestions provided a rationale directly in the document and around two-thirds of the suggestions referred to content in addition to PRISMA-P 2015 or asked for more extensive guidance than what is included.

Conclusion: The issues raised provide context to authors, peer reviewers, editors, and readers of systematic review protocols using PRISMA-P 2015 and inform the planned update of the guideline.

Objectives: To support systematic reviewers new to network meta-analysis (NMA), we (i) identified and described published methods resources for conducting systematic reviews (SRs) with NMA of randomized controlled trials (RCTs); (ii) mapped the resources to the typical steps for conducting NMA's; and (iii) identified NMA guidance gaps.

Study design and setting: We performed a scoping review and comprehensively searched major databases, grey literature sources and websites for methods resources that described or informed any steps in conducting SRs with NMA to guide review authors, particularly those new to the method. Title, abstract and full text screening were conducted independently in duplicate using Covidence. NMA resources were narratively described and tabulated by guidance type, review steps and topic and mapped to the steps of conducting a systematic review with NMA.

Results: We considered documents in the 2011-2025 date range and included 90; the majority (39%) were published between 2021-2025. Most were classified as guides/guidance (29%), methods/methodology (22%) or reviews (27%). We found that the rate of published guidance around most steps of NMA increased or remained stable over time. Most resources for software were guidance for R and Stata. Guidance documents on assumptions and certainty of evidence were abundant (in excess of 13 documents per topic), while fewer guidance documents were available on elements of protocol development and presentation of results. We mapped methods resources across steps in conducting SRs with NMA, identifying areas with sparse guidance.

Conclusion: This scoping review provides a comprehensive reference for conducting SRs using NMA, especially for those new to the methods. It highlights the significant increase in guidance since 2011, particularly on evidence certainty and NMA assumptions, and the availability of user-friendly web tools. Future work should focus on advanced NMA guidance and decision tools to aid reviewers in further navigating NMA complexities.

Historically, local progression, an outcome of effectiveness in curative radiotherapy, has not always been statistically analyzed with the same method. This article aims to elucidate the validity and relative usefulness of statistical strategies to analyze local control. In an application example, data were analyzed from a phase III trial comparing different radiation schedules for glottic cancer. The superiority of experimental treatment over standard treatment in local control was detected by a competing risks model but not detected in the analysis of local progression-free survival by a standard survival model. The use of a composite outcome, local progression-free survival, is suboptimal in that local progression and death are equally treated as the events of interest. In the analysis of local progression-free rate, by censoring death, the cumulative incidence of local progression is overestimated. We recommend the consistent use of the cumulative incidence of local progression as the endpoint to assess local control after radiotherapy.