Steven N. Goodman

COVID-19 has been reported to cause multisystem effects lasting years [Z. Al-Aly, E. Topol, Science 383, 830–832 (2024)]. These findings are primarily based on cohort studies comparing test-positive COVID-19 patients to controls without known COVID-19 infection, tested or untested [M. Cai, Y. Xie, E. J. Topol, Z. Al-Aly, Nat. Med. 30, 1564–1573 (2024)]. However, such comparisons can be biased by the reasons people were tested. Using 14.4 billion insurance claims from 244.7 million US patients, we find that most long-term effects attributed to COVID-19 by unrestricted control designs likely reflect bias due to selective testing of individuals with non-COVID conditions, causing long-term effects of those conditions to be misattributed to COVID-19. We removed this bias by analyzing only tested individuals, comparing test-positive to test-negative patients. Across 614 clinical outcomes followed over 2 y, the test-based design resulted in 83.5% fewer symptoms being attributable to COVID-19 between 30 to 119 d after infection (43 attributable symptoms vs. 262 for the unrestricted control design), a 98.2% reduction at 120 to 359 d (5 vs. 286), and a 100% reduction at 360 to 719 d (0 vs. 369). The unrestricted control design also attributed unrelated outcomes (e.g., firearm injuries) to COVID-19 at a high rate, whereas the testing-based design did not. The test-based control design may modestly underestimate some effects. This study does not indicate that symptoms beyond one year are not genuine but that their attributability to COVID-19 is uncertain.

In academia, the curriculum vitae (CV) is the central document used for hiring, promotion, or tenure applications. The content and format of these CVs and accompanying documents varies among institutions and is a direct reflection of the institution's values. Few institutions consider rigor, reproducibility, or transparency practices for hiring, promotion, or tenure decisions. We developed a new CV template for Stanford's School of Medicine for researchers to highlight their use of those practices, making it possible to evaluate faculty not just on research reports, but how they do the research itself. The new additions include listing (and linking) availability of protocols, analysis plans, analytic code, data, public accessibility of results for research outputs; registration number and result reporting for clinical trials; details of peer review activities; and candidate's persistent identifier (e.g., ORCID iD). We also include a variety of practices supporting research rigor and reproducibility that can be described in a candidate's narrative statement. For those who dedicate time and resources to maximize the rigor, reproducibility, and transparency of their work, our new CV template makes these efforts visible, a precondition for valuing them. This can serve as a model for other institutions, while future advances in scholarly metadata and systems could facilitate easier collection and reporting.

Background: Public information on US clinical trials is shared through the ClinicalTrials.gov registry. This study’s goal was to determine prospective registration, results reporting, trial registration number reporting, and publication accessibility status for trials with primary completion dates from 2014 to 2017 affiliated with seven California universities. Methods: We identified trials with investigators, sponsors, or responsible parties affiliated with seven California universities and searched for their results publications manually. We then used semi-automatic methods to determine prospective registration, summary results reporting in a registry, publication status, and reporting of registration numbers in the abstract and the full text of manuscripts. Results: We identified 1091 unique trials. Most trials were single-center ( n = 752, 69%) and had a median of 50 participants (IQR 21 to 150). Overall, 64% of trials ( n = 698) were prospectively registered, 46% ( n = 500) had summary results reported in the registry, 69% ( n = 750) had results published as articles, and an additional 3% ( n = 36) as abstracts or posters. Results reporting (summary, articles, abstracts or posters) occurred for 58% of trials ( n = 637) within 2 years, and for 81% ( n = 888) within 5 years of the study’s primary completion date. Of journal publications, 77% ( n = 579) were open access publications, 37% ( n = 276) had trial registration numbers listed in their abstract, and 45% ( n = 336) in the manuscript. Only 92 (8%) of these trials were legally required to report results, and only 2 (2%) of those were overdue and under the primary responsibility of a California university to report. Conclusions: Almost one fifth of clinical trials with primary completion dates from 2014 to 2017 with investigators, sponsors or responsible parties affiliated with seven California biomedical research universities lacked any results reporting 5 years after their primary completion, and only 58% reported results within 2 years. Even though a large majority of these trials were completed before US legal mandates for reporting, there was an ethical requirement that the burden to research participants should be commensurate with the scientific value of the research. Research has no public scientific value if its results are not reported.

Single-arm trials can be used to explore the feasibility, implementation, and effects of treatment. They typically use opportunistic convenience sampling to find potential participants. Their main limitations for health care decision making are lack of generalizability and the poor quality of the comparative evidence they produce. The authors propose a single-arm trial design that can provide greater generalizability and higher quality of comparative evidence than traditional single-arm trials, called a random invitation single-arm trial or RISAT. A RISAT has 4 essential components. First, it has a data infrastructure for routinely collected real-world data (RWD) where participants have provided consent to have their data used for research (for example, a registry or electronic medical record database). Second, a subset of those participants are randomly invited to take part in the RISAT. Those not invited are not contacted. Third, invitees are offered the specific intervention (such as a novel treatment), to which they consent or not. Fourth, all invitees are followed prospectively regardless of their acceptance of the intervention. For an optional randomized comparison, RISATs can use the RWD infrastructure to measure outcomes from invitees and noninvitees. The authors describe the advantages and challenges of this approach, including inferential issues and biases and comparison with other designs. They show how RISATs allow fairer access to participation, improve applicability and generalizability of results compared with traditional single-arm trials, and provide a form of randomized real-world evidence. At negligible added cost beyond already existing infrastructure, this approach may catalyze the early generation of evidence of higher value than that produced with traditional single-arm trials, increasing the credibility and validity of accelerated drug approval processes and enabling better health care decisions.

What is the added risk for death from smoking? Logistic regression has become the most common statistical method to answer such questions in the biomedical literature. However, the typical analyses estimate odds ratios, a metric too often misunderstood and misinterpreted. Although estimates of risks, and their differences and ratios, offer transparent clinical interpretations, commonly used statistical models have known methodological shortcomings. "Standardization" through modeling, weighting, or matching offers a solution. The goals of this article are to review classical concepts of standardization and to link them to regression modeling for causal inference. The authors also describe approaches based on weighting and matching compared with regression-based standardization. Using an example of smoking from the ARIC (Atherosclerosis Risk in Communities) study, they explain the value of standardization, long used in medicine and public health, to estimate risks and their differences and ratios for binary outcomes. The authors demonstrate how standard statistical software using models that best fit the data and respect underlying biological or clinical processes can reexpress results in clinically meaningful metrics. The Supplement offers examples with common software packages.

Importance The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Objective To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. Design We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. Findings Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Conclusions and relevance Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.

High quality protocols facilitate proper planning, conduct, reporting, and external review of randomised trials, yet their completeness varies and key elements are often not considered. To strengthen good reporting of trial protocols, the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 statement has been updated to incorporate new evidence and emerging perspectives. This SPIRIT 2025 explanation and elaboration document provides users with exemplars of reporting in contemporary trial protocols, contextual elaboration, more detailed guidance on reporting, references to key empirical studies, an expanded checklist, and a link to a website for further information. The document is intended to be used in conjunction with the SPIRIT 2025 statement and serves as a resource for researchers planning a trial and for others interested in trial protocols.

Importance: The protocol of a randomised trial is the foundation for study planning, conduct, reporting, and external review. However, trial protocols vary in their completeness and often do not address key elements of design and conduct. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) statement was first published in 2013 as guidance to improve the completeness of trial protocols. Periodic updates incorporating the latest evidence and best practices are needed to ensure that the guidance remains relevant to users. Objective: To systematically update the SPIRIT recommendations for minimum items to address in the protocol of a randomised trial. Design: We completed a scoping review and developed a project specific database of empirical and theoretical evidence to generate a list of potential changes to the SPIRIT 2013 checklist. The list was enriched with recommendations provided by lead authors of existing SPIRIT/CONSORT (Consolidated Standards of Reporting Trials) extensions (Harms, Outcomes, Non-pharmacological Treatment) and other reporting guidelines (TIDieR). The potential modifications were rated in a three-round Delphi survey followed by a consensus meeting. Findings: Overall, 317 individuals participated in the Delphi consensus process and 30 experts attended the consensus meeting. The process led to the addition of two new protocol items, revision to five items, deletion/merger of five items, and integration of key items from other relevant reporting guidelines. Notable changes include a new open science section, additional emphasis on the assessment of harms and description of interventions and comparators, and a new item on how patients and the public will be involved in trial design, conduct, and reporting. The updated SPIRIT 2025 statement consists of an evidence-based checklist of 34 minimum items to address in a trial protocol, along with a diagram illustrating the schedule of enrolment, interventions, and assessments for trial participants. To facilitate implementation, we also developed an expanded version of the SPIRIT 2025 checklist and an accompanying explanation and elaboration document. Conclusions and relevance: Widespread endorsement and adherence to the updated SPIRIT 2025 statement have the potential to enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, funders, research ethics committees, journals, trial registries, policymakers, regulators, and other reviewers.

Critical appraisal of the quality of randomised trials is possible only if their design, conduct, analysis, and results are completely and accurately reported. Without transparent reporting of the methods and results, readers will not be able to fully evaluate the reliability and validity of trial findings. The CONSORT (Consolidated Standards of Reporting Trials) statement aims to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996 and was updated in 2001 and 2010. CONSORT comprises a checklist of essential items that should be included in reports of randomised trials and a diagram for documenting the flow of participants through a trial. The CONSORT statement has been updated (CONSORT 2025) to reflect recent methodological advancements and feedback from end users, ensuring that it remains fit for purpose. Here, we present the updated CONSORT explanation and elaboration document, which has been extensively revised and describes the rationale and scientific background for each CONSORT 2025 checklist item and provides published examples of good reporting. The objective is to enhance the use, understanding, and dissemination of CONSORT 2025 and provide guidance to authors about how to improve the reporting of their trials and ensure trial reports are complete, and transparent.

Background Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. Methods We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (eg, personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. Results We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. Conclusion Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.