[Registration of national health registry-based research]. / Registrering av forskning baserad på nationella hälsoregister.

In medical research as a whole, frequent inaccurate or biased findings are of international concern. One measure against reporting biases is study registration before the start of data collection (preregistration), preferably together with the statistical analysis plan. This meta-research study systematically evaluated registration of Swedish observational research based on national health registries. In a random sample of registry-based observational studies published 2010-2022, very few were preregistered with a publicly available analysis plan (<1 procent). Ideas from the meta-research literature can be leveraged to strengthen the brand of Swedish registry-based observational studies and counteract reporting bias.

Clinical trial evidence of quality-of-life effects of disease-modifying therapies for multiple sclerosis: a systematic analysis.

BACKGROUND: Increasingly, patients, clinicians, and regulators call for more evidence on the impact of innovative medicines on quality of life (QoL). We assessed the effects of disease-modifying therapies (DMTs) on QoL in people with multiple sclerosis (PwMS). METHODS: Randomized trials assessing approved DMTs in PwMS with results for at least one outcome referred to as "quality of life" were searched in PubMed and ClinicalTrials.gov. RESULTS: We identified 38 trials published between 1999 and 2023 with a median of 531 participants (interquartile range (IQR) 202 to 941; total 23,225). The evaluated DMTs were mostly interferon-beta (n = 10; 26%), fingolimod (n = 7; 18%), natalizumab (n = 5; 13%), and glatiramer acetate (n = 4; 11%). The 38 trials used 18 different QoL instruments, with up to 11 QoL subscale measures per trial (median 2; IQR 1-3). QoL was never the single primary outcome. We identified quantitative QoL results in 24 trials (63%), and narrative statements in 15 trials (39%). In 16 trials (42%), at least one of the multiple QoL results was statistically significant. The effect sizes of the significant quantitative QoL results were large (median Cohen's d 1.02; IQR 0.3-1.7; median Hedges' g 1.01; IQR 0.3-1.69) and ranged between d 0.14 and 2.91. CONCLUSIONS: Certain DMTs have the potential to positively impact QoL of PwMS, and the assessment and reporting of QoL is suboptimal with a multitude of diverse instruments being used. There is an urgent need that design and reporting of clinical trials reflect the critical importance of QoL for PwMS.

Research rigor and reproducibility in research education: A CTSA institutional survey.

We assessed the rigor and reproducibility (R&R) activities of institutions funded by the National Center for Advancing Translational Sciences (NCTSA) through a survey and website search (N = 61). Of 50 institutional responses, 84% reported incorporating some form of R&R training, 68% reported devoted R&R training, 30% monitored R&R practices, and 10% incentivized them. Website searches revealed 9 (15%) freely available training curricula, and 7 (11%) institutional programs specifically created to enhance R&R. NCATS should formally integrate R&R principles into its translational science models and institutional requirements.

Use of pragmatic randomized trials in multiple sclerosis: A systematic overview.

BACKGROUND: Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. OBJECTIVE: The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). METHODS: Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. RESULTS: We identified 48 pragmatic trials published 1967-2022 that included a median of 82 participants (interquartile range (IQR) = 42-160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). CONCLUSION: Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence.

Few randomized trials in preterm birth prevention meet predefined usefulness criteria.

OBJECTIVES: We operationalized a research usefulness tool identified through literature searches and consensus and examined if randomized controlled trials (RCTs) addressing preterm birth prevention met predefined criteria for usefulness. STUDY DESIGN AND SETTING: The usefulness tool included eight criteria combining 13 items. RCTs were evaluated for compliance with each item by multiple assessors (reviewer agreement 95-98%). Proportions of compliances with 95% confidence interval (CI) were calculated and change over time was assessed using â‰§ 2010 as a cutoff. RESULTS: Among 347 selected RCTs, published within 56 preterm birth Cochrane reviews, only 36 (10%, 95% CI = 7-14%) met more than half of the usefulness criteria. Compared to trials before 2010, recent trials used composite or surrogate (less informative) outcomes more often (13% vs. 25%, relative risk 1.91, 95% CI = 1.21-3.00). Only 16 trials reflected real practice (pragmatism) in design (5%, 95% CI = 3-7%), with no improvements over time. No trials reported involvement of mothers to reflect patients' research priorities and outcomes selection. Recent trials were more transparent. CONCLUSION: Few preterm birth prevention RCTs met more than half of the usefulness criteria but most of usefulness criteria are improving after 2010. Use of informative outcomes, patient centeredness, pragmatism and transparency should be key targets for future research planning.

Mapping and systematic appraisal of umbrella reviews in epidemiological research: a protocol for a meta-epidemiological study.

INTRODUCTION: Umbrella review is one of the terms used to describe an overview of systematic reviews. During the last years, a rapid increase in the number of umbrella reviews on epidemiological studies has been observed, but there is no systematic assessment of their methodological and reporting characteristics. Our study aims to fill this gap by performing a systematic mapping of umbrella reviews in epidemiological research. METHODS: We will perform a meta-epidemiological study including a systematic review in MEDLINE and EMBASE to identify all the umbrella reviews that focused on systematic reviews of epidemiological studies and were published from inception until December 31, 2022. We will consider eligible any research article which was designed as an umbrella review and summarized systematic reviews and meta-analyses of epidemiological studies. From each eligible article, we will extract information about the research topic, the methodological characteristics, and the reporting characteristics. We will examine whether the umbrella reviews assessed the strength of the available evidence and the rigor of the included systematic reviews. We will also examine whether these characteristics change across time. DISCUSSION: Our study will systematically appraise the methodological and reporting characteristics of published umbrella reviews in epidemiological literature. The findings of our study can be used to improve the design and conduct of future umbrella reviews, to derive a standardized set of reporting and methodological guidelines for umbrella reviews, and to allow further meta-epidemiological work. SYSTEMATIC REVIEW REGISTRATION: osf.io/sxzc6.

[In the wake of the replication crisis, reproducibility networks take action against widespread methodological shortcomings]. / I replikationskrisens spår agerar länder mot utbredda metodbrister.

The ¼replication crisis« refers to the crisis of confidence triggered by the failure to reproduce a large portion of important findings in several scientific disciplines, including medicine. Failed replication occurred in high-profiled scandals such as the ¼omics« case at Duke University, as well as in systematic attempts to reproduce influential preclinical studies. An extensive meta-research literature attests to problems with suboptimal methods choices and indicates that behaviors bordering between deliberate misleading and well-intentioned mistakes (questionable research practices) are very common (e.g. selective reporting of particular results ¼based on a gut feeling«). As a consequence, influential international institutions have been prompted to take action to strengthen research rigor and reproducibility. So-called reproducibility networks, pioneered in the UK, seem particularly promising to organize necessary coordinated efforts among a wide range of stakeholders.

Published registry-based pharmacoepidemiologic associations show limited concordance with agnostic medication-wide analyses.

OBJECTIVES: To assess how the results of published national registry-based pharmacoepidemiology studies (where select associations are of interest) compare with an agnostic medication-wide approach (where all possible drug associations are tested). STUDY DESIGN AND SETTING: We systematically searched for publications that reported drug associations with any, breast, colon/colorectal, or prostate cancer in the Swedish Prescribed Drug Registry. Results were compared against a previously performed agnostic medication-wide study on the same registry. PROTOCOL: https://osf.io/kqj8n. RESULTS: Most published studies (25/32) investigated previously reported associations. 421/913 (46%) associations had statistically significant results. 134 of the 162 unique drug-cancer associations could be paired with 70 associations in the agnostic study (corresponding drug categories and cancer types). Published studies reported smaller effect sizes and absolute effect sizes than the agnostic study, and generally used more adjustments. Agnostic analyses were less likely to report statistically significant protective associations (based on a multiplicity-corrected threshold) than their paired associations in published studies (McNemar odds ratio 0.13, P = 0.0022). Among 162 published associations, 36 (22%) showed increased risk signal and 25 (15%) protective signal at P < 0.05, while for agnostic associations, 237 (11%) showed increased risk signal and 108 (5%) protective signal at a multiplicity-corrected threshold. Associations belonging to drug categories targeted by individual published studies vs. nontargeted had smaller average effect sizes; smaller P values; and more frequent risk signals. CONCLUSION: Published pharmacoepidemiology studies using a national registry addressed mostly previously proposed associations, were mostly "negative", and showed only modest concordance with their respective agnostic analyses in the same registry.

Differential COVID-19 infection rates in children, adults, and elderly: Systematic review and meta-analysis of 38 pre-vaccination national seroprevalence studies.

Background: Debate exists about whether extra protection of elderly and other vulnerable individuals is feasible in COVID-19. We aimed to assess the relative infection rates in the elderly vs the non-elderly and, secondarily, in children vs adults. Methods: We performed a systematic review and meta-analysis of seroprevalence studies conducted in the pre-vaccination era. We identified representative national studies without high risk of bias through SeroTracker and PubMed searches (last updated May 17, 2022). We noted seroprevalence estimates for children, non-elderly adults, and elderly adults, using cut-offs of 20 and 60 years (or as close to these ages, if they were unavailable) and compared them between different age groups. Results: We included 38 national seroprevalence studies from 36 different countries comprising 826 963 participants. Twenty-six of these studies also included pediatric populations and twenty-five were from high-income countries. The median ratio of seroprevalence in elderly vs non-elderly adults (or non-elderly in general, if pediatric and adult population data were not offered separately) was 0.90-0.95 in different analyses, with large variability across studies. In five studies (all in high-income countries), we observed significant protection of the elderly with a ratio of <0.40, with a median of 0.83 in high-income countries and 1.02 elsewhere. The median ratio of seroprevalence in children vs adults was 0.89 and only one study showed a significant ratio of <0.40. The main limitation of our study is the inaccuracies and biases in seroprevalence studies. Conclusions: Precision shielding of elderly community-dwelling populations before the availability of vaccines was indicated in some high-income countries, but most countries failed to achieve any substantial focused protection. Registration: Open Science Framework (available at: https://osf.io/xvupr).

Pre-pregnancy participation and performance in world's largest cross-country ski race as a proxy for physical exercise and fitness, and perinatal outcomes: Prospective registry-based cohort study.

OBJECTIVE: Investigate associations between pre-pregnancy participation and performance in a demanding cross-country ski race (proxy for exercise volume and fitness) and perinatal outcomes. Pre-registered protocol: osf.io/aywg2. DESIGN: Prospective cohort study. SETTING: Based on entire overlap between the Vasaloppet registry and the population-based Swedish Pregnancy Register. SAMPLE: All female Vasaloppet participants 1991-2017 with subsequent singleton delivery (skiers), and age- and county-matched non-skiers. METHODS: We calculated odds ratios (ORs) for non-skiers versus skiers (model 1) and, among skiers, by performance (model 2), in Bayesian logistic regressions adjusted for socio-demographics, lifestyle factors, and comorbidities. We repeated calculations adjusting for early pregnancy body mass index (potential mediator) and explored robustness (selection/exposure settings; multiple comparisons correction). MAIN OUTCOME MEASURES: Twenty-nine important perinatal outcomes, predefined based on existing expert consensus. RESULTS: Non-skiers (n = 194 384) versus skiers (n = 15 377) (and slower versus faster performance, not shown) consistently had higher odds of gestational diabetes mellitus (GDM) (OR 1.70, 95% highest density interval: 1.40-2.09), excessive gestational weight gain (GWG) (1.28, 1.22-1.38), psychiatric morbidity (1.60, 1.49-1.72), any caesarean section (CS) (1.34, 1.28-1.40), elective CS (1.39, 1.29-1.49), and large-for-gestational-age babies (>90th percentile, 1.11, 1.04-1.18); lower odds of inadequate GWG (0.83, 0.79-0.88); and no associations with fetal/neonatal complications (e.g. preterm birth [1.09, 0.98-1.20], small for gestational age [SGA] [1.23, 1.05-1.45]). Adjustment for body mass index attenuated associations with excessive (1.20, 1.14-1.30) and inadequate GWG (0.87, 0.83-0.92) and large for gestational age (1.07, 1.00-1.13). CONCLUSION: Non-skiers compared with skiers, and slower versus faster performance, consistently displayed higher odds of GDM, excessive GWG, psychiatric morbidity, CS and large-for-gestational-age babies; and lower odds of inadequate GWG, after adjustment for socio-demographic and lifestyle factors and comorbidities. There were no associations with fetal/neonatal complications.

Age-stratified infection fatality rate of COVID-19 in the non-elderly population.

The largest burden of COVID-19 is carried by the elderly, and persons living in nursing homes are particularly vulnerable. However, 94% of the global population is younger than 70 years and 86% is younger than 60 years. The objective of this study was to accurately estimate the infection fatality rate (IFR) of COVID-19 among non-elderly people in the absence of vaccination or prior infection. In systematic searches in SeroTracker and PubMed (protocol: https://osf.io/xvupr), we identified 40 eligible national seroprevalence studies covering 38 countries with pre-vaccination seroprevalence data. For 29 countries (24 high-income, 5 others), publicly available age-stratified COVID-19 death data and age-stratified seroprevalence information were available and were included in the primary analysis. The IFRs had a median of 0.034% (interquartile range (IQR) 0.013-0.056%) for the 0-59 years old population, and 0.095% (IQR 0.036-0.119%) for the 0-69 years old. The median IFR was 0.0003% at 0-19 years, 0.002% at 20-29 years, 0.011% at 30-39 years, 0.035% at 40-49 years, 0.123% at 50-59 years, and 0.506% at 60-69 years. IFR increases approximately 4 times every 10 years. Including data from another 9 countries with imputed age distribution of COVID-19 deaths yielded median IFR of 0.025-0.032% for 0-59 years and 0.063-0.082% for 0-69 years. Meta-regression analyses also suggested global IFR of 0.03% and 0.07%, respectively in these age groups. The current analysis suggests a much lower pre-vaccination IFR in non-elderly populations than previously suggested. Large differences did exist between countries and may reflect differences in comorbidities and other factors. These estimates provide a baseline from which to fathom further IFR declines with the widespread use of vaccination, prior infections, and evolution of new variants.

Alcohol consumption habits and associations with anxiety or depressive symptoms postpartum in women with high socioeconomic status in Sweden.

Postpar tum depression and anxiety are common among new mothers. It is well-established that in the general population alcohol use is associated with depression and anxiety. Linking alcohol consumption to symptoms of postpartum depression (PPDS) or postpartum anxiety (PPAS) is presently less established. This study aims to determine if alcohol consumption pre-pregnancy, 6 weeks postpartum, 6 months postpartum, or changes in alcohol consumption are associated with PPDS or PPAS. Longitudinal data on 3849 women from a Swedish perinatal cohort were analyzed using logistic regression analyses for associations between alcohol consumption and symptoms of anxiety or depression, as assessed with the Edinburgh Postnatal Depression Scale. There was no association between pre-pregnancy drinking habits and PPDS (p = 0.588, n = 2479) or PPAS (p = 0.942; n = 2449) at 6 weeks postpartum. Similarly, no associations were observed between concurrent drinking habits at 6 weeks postpartum and PPAS (p = 0.070, n = 3626), 6 months postpartum and PPDS (0.647, n = 3461) or PPAS (p = 0.700, n = 3431). However, there was an association between drinking habits at 6 weeks postpartum and concurrent PPDS (p = 0.047, n = 3659). In conclusion, robust associations were not found between postpartum alcohol consumption and mood symptoms. This lack of association between poor mental health and risk behaviors in new mothers could be interpreted as a result of long-term policy work and high participation in Swedish maternity care. Future studies need to address these research questions in more diverse socio-cultural contexts.

Causal and Associational Language in Observational Health Research: A Systematic Evaluation.

We estimated the degree to which language used in the high-profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality. We searched for and screened 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, 3 reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations. Reviewers rated the causal implication of exposure/outcome linking language as none (no causal implication) in 13.8%, weak in 34.2%, moderate in 33.2%, and strong in 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was "associate" (45.7%). Reviewers' ratings of linking word roots were highly heterogeneous; over half of reviewers rated "association" as having at least some causal implication. This research undercuts the assumption that avoiding "causal" words leads to clarity of interpretation in medical research.

Predicting perinatal health outcomes using smartphone-based digital phenotyping and machine learning in a prospective Swedish cohort (Mom2B): study protocol.

INTRODUCTION: Perinatal complications, such as perinatal depression and preterm birth, are major causes of morbidity and mortality for the mother and the child. Prediction of high risk can allow for early delivery of existing interventions for prevention. This ongoing study aims to use digital phenotyping data from the Mom2B smartphone application to develop models to predict women at high risk for mental and somatic complications. METHODS AND ANALYSIS: All Swedish-speaking women over 18 years, who are either pregnant or within 3 months postpartum are eligible to participate by downloading the Mom2B smartphone app. We aim to recruit at least 5000 participants with completed outcome measures. Throughout the pregnancy and within the first year postpartum, both active and passive data are collected via the app in an effort to establish a participant's digital phenotype. Active data collection consists of surveys related to participant background information, mental and physical health, lifestyle, and social circumstances, as well as voice recordings. Participants' general smartphone activity, geographical movement patterns, social media activity and cognitive patterns can be estimated through passive data collection from smartphone sensors and activity logs. The outcomes will be measured using surveys, such as the Edinburgh Postnatal Depression Scale, and through linkage to national registers, from where information on registered clinical diagnoses and received care, including prescribed medication, can be obtained. Advanced machine learning and deep learning techniques will be applied to these multimodal data in order to develop accurate algorithms for the prediction of perinatal depression and preterm birth. In this way, earlier intervention may be possible. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Swedish Ethical Review Authority (dnr: 2019/01170, with amendments), and the project fully fulfils the General Data Protection Regulation (GDPR) requirements. All participants provide consent to participate and can withdraw their participation at any time. Results from this project will be disseminated in international peer-reviewed journals and presented in relevant conferences.

Infection fatality rate of COVID-19 in community-dwelling elderly populations.

This mixed design synthesis aimed to estimate the infection fatality rate (IFR) of Coronavirus Disease 2019 (COVID-19) in community-dwelling elderly populations and other age groups from seroprevalence studies. Protocol: https://osf.io/47cgb . Eligible were seroprevalence studies done in 2020 and identified by any of four existing systematic reviews; with ≥ 500 participants aged ≥ 70 years; presenting seroprevalence in elderly people; aimed to generate samples reflecting the general population; and whose location had available data on cumulative COVID-19 deaths in elderly (primary cutoff ≥ 70 years; ≥ 65 or ≥ 60 also eligible). We extracted the most fully adjusted (if unavailable, unadjusted) seroprevalence estimates; age- and residence-stratified cumulative COVID-19 deaths (until 1 week after the seroprevalence sampling midpoint) from official reports; and population statistics, to calculate IFRs adjusted for test performance. Sample size-weighted IFRs were estimated for countries with multiple estimates. Thirteen seroprevalence surveys representing 11 high-income countries were included in the main analysis. Median IFR in community-dwelling elderly and elderly overall was 2.9% (range 1.8-9.7%) and 4.5% (range 2.5-16.7%) without accounting for seroreversion (2.2% and 4.0%, respectively, accounting for 5% monthly seroreversion). Multiple sensitivity analyses yielded similar results. IFR was higher with larger proportions of people > 85 years. The IFR of COVID-19 in community-dwelling elderly is lower than previously reported.

Problems with evidence assessment in COVID-19 health policy impact evaluation: a systematic review of study design and evidence strength.

INTRODUCTION: Assessing the impact of COVID-19 policy is critical for informing future policies. However, there are concerns about the overall strength of COVID-19 impact evaluation studies given the circumstances for evaluation and concerns about the publication environment. METHODS: We included studies that were primarily designed to estimate the quantitative impact of one or more implemented COVID-19 policies on direct SARS-CoV-2 and COVID-19 outcomes. After searching PubMed for peer-reviewed articles published on 26 November 2020 or earlier and screening, all studies were reviewed by three reviewers first independently and then to consensus. The review tool was based on previously developed and released review guidance for COVID-19 policy impact evaluation. RESULTS: After 102 articles were identified as potentially meeting inclusion criteria, we identified 36 published articles that evaluated the quantitative impact of COVID-19 policies on direct COVID-19 outcomes. Nine studies were set aside because the study design was considered inappropriate for COVID-19 policy impact evaluation (n=8 pre/post; n=1 cross-sectional), and 27 articles were given a full consensus assessment. 20/27 met criteria for graphical display of data, 5/27 for functional form, 19/27 for timing between policy implementation and impact, and only 3/27 for concurrent changes to the outcomes. Only 4/27 were rated as overall appropriate. Including the 9 studies set aside, reviewers found that only four of the 36 identified published and peer-reviewed health policy impact evaluation studies passed a set of key design checks for identifying the causal impact of policies on COVID-19 outcomes. DISCUSSION: The reviewed literature directly evaluating the impact of COVID-19 policies largely failed to meet key design criteria for inference of sufficient rigour to be actionable by policy-makers. More reliable evidence review is needed to both identify and produce policy-actionable evidence, alongside the recognition that actionable evidence is often unlikely to be feasible.