Projections of incident atherosclerotic cardiovascular disease and incident type 2 diabetes across evolving statin treatment guidelines and recommendations: A modelling study.

BACKGROUND: Experimental and observational research has suggested the potential for increased type 2 diabetes (T2D) risk among populations taking statins for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, few studies have directly compared statin-associated benefits and harms or examined heterogeneity by population subgroups or assumed treatment effect. Thus, we compared ASCVD risk reduction and T2D incidence increases across 3 statin treatment guidelines or recommendations among adults without a history of ASCVD or T2D who were eligible for statin treatment initiation. METHODS AND FINDINGS: Simulations were conducted using Markov models that integrated data from contemporary population-based studies of non-Hispanic African American and white adults aged 40-75 years with published meta-analyses. Statin treatment eligibility was determined by predicted 10-year ASCVD risk (5%, 7.5%, or 10%). We calculated the number needed to treat (NNT) to prevent one ASCVD event and the number needed to harm (NNH) to incur one incident case of T2D. The likelihood to be helped or harmed (LHH) was calculated as ratio of NNH to NNT. Heterogeneity in statin-associated benefit was examined by sex, age, and statin-associated T2D relative risk (RR) (range: 1.11-1.55). A total of 61,125,042 U.S. adults (58.5% female; 89.4% white; mean age = 54.7 years) composed our primary prevention population, among whom 13-28 million adults were eligible for statin initiation. Overall, the number of ASCVD events prevented was at least twice as large as the number of incident cases of T2D incurred (LHH range: 2.26-2.90). However, the number of T2D cases incurred surpassed the number of ASCVD events prevented when higher statin-associated T2D RRs were assumed (LHH range: 0.72-0.94). In addition, females (LHH range: 1.74-2.40) and adults aged 40-50 years (LHH range: 1.00-1.14) received lower absolute benefits of statin treatment compared with males (LHH range: 2.55-3.00) and adults aged 70-75 years (LHH range: 3.95-3.96). Projected differences in LHH by age and sex became more pronounced as statin-associated T2D RR increased, with a majority of scenarios projecting LHHs < 1 for females and adults aged 40-50 years. This study's primary limitation was uncertainty in estimates of statin-associated T2D risk, highlighting areas in which additional clinical and public health research is needed. CONCLUSIONS: Our projections suggest that females and younger adult populations shoulder the highest relative burden of statin-associated T2D risk.

Observational human studies in allergic diseases: design concepts and highlights of recent National Institute of Allergy and Infectious Diseases-funded research.

PURPOSE OF REVIEW: To present and discuss key design concepts for optimizing the impact of observational studies in the field of allergy and to highlight recent findings from NIAID-funded research networks. RECENT FINDINGS: We discuss three concepts. First, the benefit of prospective, longitudinal observational studies exemplified by recent findings on the seasonal nature of all rhinitis phenotypes in children with asthma and the protective effects of high house dust allergen content during the first year of life on the development of asthma at age 7 years. Second, the benefit of detailed (deep) phenotyping exemplified by the identification of a MALT1 gene variant as a strong genetic link to peanut allergy and the determination that atopic dermatitis with food allergy constitutes a distinct cutaneous endotype, compared with atopic dermatitis alone. Third, the benefit of hypothesis-generating research combined with prospective design and deep phenotyping as exemplified by the unveiling of potential pathophysiologic pathways leading to asthma exacerbations in children, after a 'cold'. SUMMARY: Observational studies can be highly impactful if designed well. Longitudinal study design, deep phenotyping, and hypothesis-generating research are three major design concepts that should be considered in the development of these studies.

Value-Based Care for Musculoskeletal Pain: Are Physical Therapists Ready to Deliver?

Early physical therapy models hold great promise for delivering high-value care for individuals with musculoskeletal pain. However, existing physical therapist practice and research standards are misaligned with value-based principles, which limits the potential for growth and sustainability of these models. This Perspective describes how the value proposition of early physical therapy can be improved by redefining harm, embracing a prognostic approach to clinical decision making, and advocating for system-wide guideline-adherent pain care. It also outlines the need to adopt a common language to describe these models and embrace new, rigorous study designs and analytical approaches to better understand where and how early physical therapy delivers value. The goal is to define a clear path forward to ensure physical therapists are aligned within health care systems to deliver on the American Physical Therapy Association's vision of high-value care in a rapidly changing health care environment.

Emerging Challenges and Opportunities in Infectious Disease Epidemiology.

Much of the intellectual tradition of modern epidemiology stems from efforts to understand and combat chronic diseases persisting through the 20th century epidemiologic transition of countries such as the United States and United Kingdom. After decades of relative obscurity, infectious disease epidemiology has undergone an intellectual rebirth in recent years amid increasing recognition of the threat posed by both new and familiar pathogens. Here, we review the emerging coalescence of infectious disease epidemiology around a core set of study designs and statistical methods bearing little resemblance to the chronic disease epidemiology toolkit. We offer our outlook on challenges and opportunities facing the field, including the integration of novel molecular and digital information sources into disease surveillance, the assimilation of such data into models of pathogen spread, and the increasing contribution of models to public health practice. We next consider emerging paradigms in causal inference for infectious diseases, ranging from approaches to evaluating vaccines and antimicrobial therapies to the task of ascribing clinical syndromes to etiologic microorganisms, an age-old problem transformed by our increasing ability to characterize human-associated microbiota. These areas represent an increasingly important component of epidemiology training programs for future generations of researchers and practitioners.

An Assessment of the Change in Compliance of Observational Otology and Audiology Studies With the STROBE Statement Guidelines: A Systematic Review.

OBJECTIVES: Observational studies often represent the best available evidence for surgical practice. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations were generated in 2007 with the aim of improving the quality of reporting. This study was designed to assess whether publication of STROBE guidelines has improved the quality of reporting in observational otology and audiology studies. DATA SOURCES: EMBASE and MEDLINE were searched using a comprehensive keyword search developed in conjunction with a scientific librarian. STUDY SELECTION: English language papers from six Otorhinolaryngology journals during two 6-month periods (2005 and 2016) were evaluated. DATA EXTRACTION: Two reviewers independently analyzed papers according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SYNTHESIS: Percentage scores for the two periods were compared using Mann-Whitney U test. CONCLUSIONS: Forty and 42 studies were returned for the 2005 and 2016 periods, respectively. The mean percentage of STROBE items that were met improved between 2005 and 2016 (58, 76%, respectively; p < 0.0001). Analysis indicated that improvements were greater in journals that endorsed STROBE guidelines (p = 0.02). This data suggests that STROBE has increased the reporting quality of observational studies; however, there are still significant further improvements to be met.

GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence.

OBJECTIVE: To provide guidance on how systematic review authors, guideline developers, and health technology assessment practitioners should approach the use of the risk of bias in nonrandomized studies of interventions (ROBINS-I) tool as a part of GRADE's certainty rating process. STUDY DESIGN AND SETTING: The study design and setting comprised iterative discussions, testing in systematic reviews, and presentation at GRADE working group meetings with feedback from the GRADE working group. RESULTS: We describe where to start the initial assessment of a body of evidence with the use of ROBINS-I and where one would anticipate the final rating would end up. The GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains: large effects, dose-effect relations, and when plausible residual confounders or other biases increase certainty. They will need to be considered in an assessment of a body of evidence when using ROBINS-I. CONCLUSIONS: The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias. Challenges remain, including appropriate presentation of evidence from RCTs and NRSs for decision-making and how to optimally integrate RCTs and NRSs in an evidence assessment.

Doubly robust matching estimators for high dimensional confounding adjustment.

Valid estimation of treatment effects from observational data requires proper control of confounding. If the number of covariates is large relative to the number of observations, then controlling for all available covariates is infeasible. In cases where a sparsity condition holds, variable selection or penalization can reduce the dimension of the covariate space in a manner that allows for valid estimation of treatment effects. In this article, we propose matching on both the estimated propensity score and the estimated prognostic scores when the number of covariates is large relative to the number of observations. We derive asymptotic results for the matching estimator and show that it is doubly robust in the sense that only one of the two score models need be correct to obtain a consistent estimator. We show via simulation its effectiveness in controlling for confounding and highlight its potential to address nonlinear confounding. Finally, we apply the proposed procedure to analyze the effect of gender on prescription opioid use using insurance claims data.

Most response-inducing strategies do not increase participation in observational studies: a systematic review and meta-analysis.

OBJECTIVES: To evaluate response-inducing strategies for observational studies using health-related questionnaires or interviews. STUDY DESIGN AND SETTING: We searched PubMed, EMBASE, CINAHL, PsycINFO, and Web of Science up to December 28, 2017. Studies evaluating the effect of a response-inducing strategy on participation rates of observational studies were included. For each strategy, we estimated pooled response ratios with 95% confidence intervals (CIs) in a Hartung-Knapp/Sidik-Jonkman random effects model with the final participation rate as outcome, stratified for type of participants and method of data collection. RESULTS: The search yielded 168 eligible studies involving 367,616 potential participants and 33 strategies. Among patients, response-inducing strategies for paper-based questionnaires included unconditional monetary incentives (response ratio 1.15; 95% CI 1.09-1.21) and shorter questionnaires (1.04; 1.02-1.06). Among nonpatients, a personalized mode of delivery (1.47; 1.24-1.74), more expensive mailing type (1.25; 1.00-1.56), unconditional monetary incentives (1.24; 1.12-1.38), prenotification (1.12; 1.03-1.22), unconditional scratch lottery tickets (1.09; 1.01-1.18), and shorter questionnaires (1.06; 1.02-1.11) increased response rates to paper-based questionnaires. For Web-based questionnaires and interviews among nonpatients, response rates were increased by conditional lottery tickets (1.17; 1.02-1.34) and conditional monetary incentives (1.39; 1.01-1.91), respectively. CONCLUSION: Although the majority of strategies evaluated were unsuccessful, some may increase response rates to observational studies, particularly among nonpatients.

Middle Childhood Attachment Strategies: validation of an observational measure.

The purpose of this study was to assess behavioral manifestations of attachment in middle childhood, and to evaluate their relations with key theoretical correlates. The sample consisted of 87 children (aged 10-12 years) and their mothers. Dyads participated in an 8-min videotaped discussion of a conflict in their relationships, later scored with the Middle Childhood Attachment Strategies Coding System (MCAS) for key features of all child attachment patterns described in previous literature (secure, ambivalent, avoidant, disorganized-disoriented, caregiving/role-confused, hostile/punitive). To assess validity, relations among MCAS dimensions and other measures of attachment, parenting, and psychological adjustment were evaluated. Results provide preliminary evidence for the psychometric properties of the MCAS in that its behaviorally assessed patterns were associated with theoretically relevant constructs, including maternal warmth/acceptance and psychological control, and children's social competence, depression, and behavioral problems. The MCAS opens new grounds for expanding our understanding of attachment and its outcomes in middle childhood.

HIV and herpes simplex virus type 2 epidemiological synergy: misguided observational evidence? A modelling study.

OBJECTIVES: To investigate whether observational studies of HIV and herpes simplex virus type 2 (HSV-2) infections have the capacity to assess the HIV/HSV-2 epidemiological synergy. METHODS: An individual-based Monte Carlo model was used to simulate HIV/HSV-2 epidemics in two scenarios: no HIV/HSV-2 biological interaction and HSV-2 seropositivity enhancing HIV acquisition. Cross-sectional observational studies were simulated by sampling individuals from the population to assess resulting crude and adjusted ORs of the HIV/HSV-2 association. Meta-analyses were conducted to estimate the pooled mean ORs. Impact of under-reporting of sexual behaviour and miscapture of high-risk individuals was assessed through sensitivity analyses. RESULTS: Assuming no HIV/HSV-2 biological interaction, the crude HIV/HSV-2 OR ranged between 1.38 and 9.93, with a pooled mean of 6.45 (95% CI 5.81 to 7.17). Adjustment for the number of sexual partners over last year, over lifetime and for both partner numbers simultaneously reduced the mean OR to 5.45 (95% CI 4.90 to 6.06), 3.70 (95% CI 3.32 to 4.12) and 3.54 (95% CI 3.17 to 3.94), respectively. Assuming HIV/HSV-2 biological interaction, the crude OR ranged between 3.44 and 9.95, with a pooled mean of 8.05 (95% CI 7.14 to 9.07). The adjustments reduced the mean OR to 7.00 (95% CI 6.21 to 7.90), 3.76 (95% CI 3.32 to 4.25) and 3.68 (95% CI 3.25 to 4.17), respectively. Under-reporting of partners reduced the confounder-adjustment effects. Miscapture of high-risk individuals considerably lowered the estimated ORs. CONCLUSIONS: It is difficult to control for sexual-behaviour confounding in observational studies. The observed HIV/HSV-2 association appears more consistent with two infections sharing the same mode of transmission, rather than with HSV-2 enhancing HIV acquisition.

The STROBE extensions: protocol for a qualitative assessment of content and a survey of endorsement.

INTRODUCTION: The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) Statement was developed in response to inadequate reporting of observational studies. In recent years, several extensions to STROBE have been created to provide more nuanced field-specific guidance for authors. The content and the prevalence of extension endorsement have not yet been assessed. Accordingly, there are two aims: (1) to classify changes made in the extensions to identify strengths and weaknesses of the original STROBE checklist and (2) to determine the prevalence and typology of endorsement by journals in fields related to extensions. METHODS AND ANALYSIS: Two independent researchers will assess additions in each extension. Additions will be coded as 'field specific' (FS) or 'not field specific' (NFS). FS is defined as particularly relevant information for a single field and guidance provided generally cannot be extrapolated beyond that field. NFS is defined as information that reflects epidemiological or methodological tenets and can be generalised to most, if not all, types of observational research studies. Intraclass correlation will be calculated to measure reviewers' concordance. On disagreement, consensus will be sought. Individual additions will be grouped by STROBE checklist items to identify the frequency and distribution of changes.Journals in fields related to extensions will be identified through National Library of Medicine PubMed Broad Subject Terms, screened for eligibility and further distilled via Ovid MEDLINE® search strategies for observational studies. Text describing endorsement will be extracted from each journal's website. A classification scheme will be created for endorsement types and the prevalence of endorsement will be estimated. Analyses will use NVivo V.11 and SAS University Edition. ETHICS AND DISSEMINATION: This study does not require ethical approval as it does not involve human participants. This study has been preregistered on Open Science Framework.

Evidence for strategies that improve recruitment and retention of adults aged 65 years and over in randomised trials and observational studies: a systematic review.

Background: adults aged ≥65 years are often excluded from health research studies. Lack of representation reduces generalisability of treatments for this age group. Objective: to evaluate the effectiveness of strategies that improve recruitment and retention of adults aged ≥65 in observational studies and randomised controlled trials (RCTs). Methods: searches conducted in 10 databases for RCTs of recruitment and retention strategies in RCTs or observational studies. Two reviewers screened abstracts and full-text articles for eligibility and extracted data. Studies without separate data for adults aged ≥65 were discarded. Risk of bias assessed using the Cochrane Risk of Bias tool. Results were synthesised narratively. Results: thirty-two studies were included in the review (n = 75,444). Twelve studies had low risk of bias, of which 10 had successful strategies including: Opt-out versus opt-in increased recruitment (13.6% (n = 261)-18.7% (n = 36) difference; two studies); Advance notification increased retention (1.6% difference, OR 1.45; 95% CI 1.01, 2.10, one study (n = 2,686); 9.1% difference at 4 months, 1.44; 1.08, 1.92, one study (n = 753)); Hand-delivered versus postal surveys increased response (25.1% difference; X2 = 11.40, P < 0.01; one study (n = 139)); Open randomised design versus blinded RCT increased recruitment (1.56; 1.05, 2.33) and retention (13.9% difference; 3.1%, 24.6%) in one study (n = 538). Risk of bias was high/unclear for studies in which incentives or shorter length questionnaires increased response. Discussion: in low risk of bias studies, few of the strategies that improved participation in older adults had been tested in ≥1 study. Opt-out and advance notification strategies improved recruitment and retention, respectively, although an opt-out approach may have ethical limitations. Evidence from single studies limits the generalisability of other strategies.

Observational Studies Fill a Void Left by RCTs.

There is momentum building to use observational studies to investigate the safety and efficacy of medications in new ways. Drug companies are using them to establish the value of medicines in negotiating prices, rebates, and formulary placement with payers.

Establishing Evidence-Based Indications for Proton Therapy: An Overview of Current Clinical Trials.

PURPOSE: To review and assess ongoing proton beam therapy (PBT) clinical trials and to identify major gaps. METHODS AND MATERIALS: Active PBT clinical trials were identified from clinicaltrials.gov and the World Health Organization International Clinical Trials Platform Registry. Data on clinical trial disease site, age group, projected patient enrollment, expected start and end dates, study type, and funding source were extracted. RESULTS: A total of 122 active PBT clinical trials were identified, with target enrollment of >42,000 patients worldwide. Ninety-six trials (79%), with a median planned sample size of 68, were classified as interventional studies. Observational studies accounted for 21% of trials but 71% (n=29,852) of planned patient enrollment. The most common PBT clinical trials focus on gastrointestinal tract tumors (21%, n=26), tumors of the central nervous system (15%, n=18), and prostate cancer (12%, n=15). Five active studies (lung, esophagus, head and neck, prostate, breast) will randomize patients between protons and photons, and 3 will randomize patients between protons and carbon ion therapy. CONCLUSIONS: The PBT clinical trial portfolio is expanding rapidly. Although the majority of ongoing studies are interventional, the majority of patients will be accrued to observational studies. Future efforts should focus on strategies to encourage optimal patient enrollment and retention, with an emphasis on randomized, controlled trials, which will require support from third-party payers. Results of ongoing PBT studies should be evaluated in terms of comparative effectiveness, as well as incremental effectiveness and value offered by PBT in comparison with conventional radiation modalities.

Cautionary tales in the interpretation of observational studies of effects of clinical interventions.

Observational studies of the effectiveness of clinical interventions are proliferating as more 'real-world' clinical data (so called 'big data') are gathered from clinical registries, administrative datasets and electronic health records. While well-conducted randomised controlled trials (RCT) remain the scientific standard in assessing the efficacy of clinical interventions, well-designed observational studies may add to the evidence base of effectiveness in situations where RCT are of limited value or very difficult to perform. Rather than dismissing observational studies, we need to determine what circumstances may justify doing an observational study and when the study is sufficiently rigorous to be considered reasonably trustworthy. This article proposes criteria by which users of the literature might make such determinations.

A suggestion for quality assessment in systematic reviews of observational studies in nutritional epidemiology.

OBJECTIVES: It is important to control the quality level of the observational studies in conducting meta-analyses. The Newcastle-Ottawa Scale (NOS) is a representative tool used for this purpose. We investigated the relationship between high-quality (HQ) defined using NOS and the results of subgroup analysis according to study design. METHODS: We selected systematic review studies with meta-analysis which performed a quality evaluation on observational studies of diet and cancer by NOS. HQ determinations and the distribution of study designs were examined. Subgroup analyses according to quality level as defined by the NOS were also extracted. Equivalence was evaluated based on the summary effect size (sES) and 95% confidence intervals computed in the subgroup analysis. RESULTS: The meta-analysis results of the HQ and cohort groups were identical. The overall sES, which was obtained by combining the sES when equivalence was observed between the cohort and case-control groups, also showed equivalence. CONCLUSIONS: The results of this study suggest that it is more reasonable to control for quality level by performing subgroup analysis according to study design rather than by using HQ based on the NOS quality assessment tool.

Benchmarking Controlled Trial--a novel concept covering all observational effectiveness studies.

The Benchmarking Controlled Trial (BCT) is a novel concept which covers all observational studies aiming to assess effectiveness. BCTs provide evidence of the comparative effectiveness between health service providers, and of effectiveness due to particular features of the health and social care systems. BCTs complement randomized controlled trials (RCTs) as the sources of evidence on effectiveness. This paper presents a definition of the BCT; compares the position of BCTs in assessing effectiveness with that of RCTs; presents a checklist for assessing methodological validity of a BCT; and pilot-tests the checklist with BCTs published recently in the leading medical journals.

Challenges in assessing the process-outcome link in practice.

The expanded use of clinical process-of-care measures to assess the quality of health care in the context of public reporting and pay-for-performance applications has led to a desire to demonstrate the value of such efforts in terms of improved patient outcomes. The inability to observe associations between improved delivery of clinical processes and improved clinical outcomes in practice has raised concerns about the value of holding providers accountable for delivery of clinical processes of care. Analyses that attempt to investigate this relationship are fraught with many challenges, including selection of an appropriate outcome, the proximity of the outcome to the receipt of the clinical process, limited power to detect an effect, small expected effect sizes in practice, potential bias due to unmeasured confounding factors, and difficulties due to changes in measure specification over time. To avoid potentially misleading conclusions about an observed or lack of observed association between a clinical process of care and an outcome in the context of observational studies, individuals conducting and interpreting such studies should carefully consider, evaluate, and acknowledge these types of challenges.

[Registration of observational studies: it is time to comply with the Declaration of Helsinki requirement]. / El registro de los estudios observacionales: es el momento de cumplir el requerimiento de la Declaración de Helsinki.

Publication bias is a serious deficiency in the current system of disseminating the results of human research studies. Clinical investigators know that, from an ethical standpoint, they should prospectively register clinical trials in a public registry before starting them. In addition, it is believed that this approach will help to reduce publication bias. However, most studies conducted in humans are observational rather than experimental. It is estimated that less than 2% out of 2 million concluded or ongoing observational studies have been registered. The 2013 revision of the Declaration of Helsinki requires registration of any type of research study involving humans or identifiable samples or data. It is proposed that funding agencies, such as the Fondo de Investigaciones Sanitarias, as well as private companies, require preregistration of observational studies before providing funding. It is also proposed that Research Ethics Committees which, following Spanish regulation, have been using the Declaration as the framework for assessing the ethics of clinical trials with medicines since 1990, should follow the same provisions for the assessment of health-related observational studies: therefore, they should require prospective registration of studies before granting their final approval. This would allow observational study investigators to be educated in complying with an ethical requirement recently introduced in the most important ethical code for research involving humans.