Target trial framework for determining the effect of changes in training load on injury risk using observational data: a methodological commentary.

In recent years, a large focus has been placed on managing training load for injury prevention. To minimise injuries, training recommendations should be based on research that examines causal relationships between load and injury risk. While observational studies can be used to estimate causal effects, conventional methods to study the relationship between load and injury are prone to bias. The target trial framework is a valuable tool that requires researchers to emulate a hypothetical randomised trial using observational data. This framework helps to explicitly define research questions and design studies in a way that estimates causal effects. This article provides an overview of the components of the target trial framework as applied to studies on load and injury and describes various considerations that should be made in study design and analyses to minimise bias.

Principles of musculoskeletal sport injuries for epidemiologists: a review.

BACKGROUND: Musculoskeletal injuries are a common occurrence in sport. The goal of sport injury epidemiology is to study these injuries at a population level to inform their prevention and treatment. MAIN BODY: This review provides an overview of musculoskeletal sport injuries and the musculoskeletal system from a biological and epidemiologic perspective, including injury mechanism, categorizations and types of sport injuries, healing, and subsequent injuries. It is meant to provide a concise introductory substantive background of musculoskeletal sport injuries for epidemiologists who may not have formal training in the underlying anatomy and pathophysiology. CONCLUSION: An understanding of sport injuries is important for researchers in sport injury epidemiology when determining how to best define and assess their research questions and measures.

Effect modification of cancer on the association between dysphagia and mortality in early idiopathic inflammatory myopathies.

OBJECTIVE: The interplay between dysphagia, cancer, and mortality in idiopathic inflammatory myopathies (IIM) has not been carefully studied. The aim of this study was to investigate possible effect modification of cancer on the association between dysphagia and mortality in early IIM. METHODS: A multi-center cohort of 230 adult IIM patients with dysphagia assessment within 6 months of disease onset was assembled. Crude mortality rates in IIM patients exposed or not to dysphagia were estimated for the 5-year period following cohort entry. To explore possible effect modification of cancer on the association between dysphagia and mortality, adjusted Cox models stratified on cancer status were performed as well as an interaction model. RESULTS: Mortality rates per 100 person-years for IIM patients exposed to dysphagia were 2.3 (95 %CI 1.0 to 4.5) in those without cancer compared to 33.3 (95 %CI 16.6 to 59.5) in those with cancer. In stratified Cox models, the main effect of dysphagia was HR 0.5 (95 %CI 0.2 to 1.5) in non-cancer and 3.1 (95 %CI 1.0 to 10.2) in cancer patients. In the interaction model, the combination of dysphagia and cancer yielded a HR of 6.4 (1.2 to 35.1). CONCLUSION: In this IIM cohort, dysphagia in non-cancer patients was not associated with increased mortality, while it was in presence of cancer, supporting effect modification of cancer on the association between dysphagia and mortality. This suggests that IIM patients with and without cancer differ and separate analyses for the two groups should be conducted when the outcome of interest is mortality.

Investigating the Effect of Return-to-Play Timing After Injury on Performance: Does the Analysis Answer the Research Objective?

Return-to-play decision making should be based on all the advantages and disadvantages of return to play for athletes, not just the risk of injury. For competitive athletes, this includes the effect of early versus delayed return to sport on performance. In this paper, we address the questions "How can I estimate the effect of injury on the individual's performance at return to play?" and "What is the effect of delaying return to sport on the individual's performance?". To address these questions, we describe (1) some foundational concepts, design and analytical challenges related to estimating the causal effect of return to play timing on performance in the athlete, (2) additional challenges if one is interested in the effects of delaying return to play and (3) differences when the questions relate to the team's performance. Although the analytical strategies described appear complicated, coaches and athletes make these judgements informally every day without explicitly stating their assumptions. Using a formal approach should help analysts provide the most valid answers to the questions asked by athletes and coaches. In brief, the choice of a comparison group depends on the research question and requires that one consider the hypothetical performance trajectory of the athlete had they never been injured. Thus, the optimal comparison group depends on the shape of the expected trajectory and the specific research question being asked.

Implementing Multiple Imputation for Missing Data in Longitudinal Studies When Models are Not Feasible: An Example Using the Random Hot Deck Approach.

Purpose: Researchers often use model-based multiple imputation to handle missing at random data to minimize bias. However, constraints within the data may sometimes result in implausible values, making model-based imputation infeasible. In these contexts, we illustrate how random hot deck imputation can allow for plausible multiple imputation in longitudinal studies. Patients and Methods: Our motivating example is the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS-DK), a prospective cohort study that measured weekly sports participation for 1700 Danish schoolchildren. Using observed data on 4 variables (pain, activity frequency, sport, sport counts), we created a gold-standard data set without missing data. We then created a synthetic data set by setting some variable values to missing based on a prediction model that mimicked real-data missingness patterns. To create 5 imputed data sets, we matched each record with missing data to several fully observed records, generated probabilities from matched records, and sampled from these records based on the probability of each occurring. We assessed variability and agreement (kappa) between the imputed data sets and the gold-standard data set. We compare results to common model-based imputation methods. Results: Variability across data sets appeared reasonable. The range of kappa for the random hot deck approach was moderate for activity frequency (0.65 to 0.71) and sport (0.59 to 0.85), and poor for common model-based approaches (range 0.00 to 0.11). The range of kappas for sport count was strong (0.87 to 0.97) for random hot deck imputation and weak to moderate (0.55 to 0.71) for common model-based imputation. Agreement was higher when more information was present, and when prevalence was higher for our binary variable sport. Conclusion: Random hot deck imputation should be considered as an alternative method when model-based approaches are infeasible, specifically where there are constraints within and between covariates.

Observed Injury Rates Did Not Follow Theoretically Predicted Injury Risk Patterns in Professional Human Circus Artists.

OBJECTIVE: Identifying which types of athletes have increased injury risk (ie, predictive risk factors) should help develop cost-effective selective injury prevention strategies. Our objective was to compare a theoretical injury risk classification system developed by coaches and rehabilitation therapists, with observed injury rates in human circus acts across dimensions of physical stressors, acrobatic complexity, qualifications, and residual risks. DESIGN: Descriptive epidemiological study. SETTING: professional circus company. PATIENTS OR OTHER PARTICIPANTS: Human circus artists performing in routine roles between 2007 and 2017. ASSESSMENT OF RISK FACTORS: Characteristics of circus acts categorized according to 4 different dimensions. MAIN OUTCOME MEASURES: Medical attention injury rates (injury requiring a visit to the therapist), time-loss injury rates (TL-1; injury resulting in at least one missed performance), and time-loss 15 injury rates (TL-15; injury resulting in at least 15 missed performances). RESULTS: Among 962 artists with 1 373 572 performances, 89.4% (860/962) incurred at least one medical attention injury, 74.2% (714/962) incurred at least one TL-1 injury, and 50.8% (489/962) incurred at least one TL-15 injury. There were important inconsistencies between theoretical and observed injury risk patterns in each of the 4 dimensions for all injury definitions (medical attention, TL-1, and TL-15). CONCLUSIONS: Although theoretical classifications are the only option when no data are available, observed risk patterns based on injury surveillance programs can help identify artists who have a high (or low) theoretical risk but are nonetheless actually at low (or high) risk of injury, given their current roles. This will help develop more cost-effective selective injury prevention programs.

Causal effects, workload and injury risk: The importance of specifying the research question.

OBJECTIVES: To illustrate why the research question determines whether and how sport medicine investigators should adjust for workload when interested in interventions or causal risk factors for injury. DESIGN: Theoretical conceptualization. METHODS: We use current concepts of causal inference to demonstrate the advantages and disadvantages of adjusting for workload through different analytic approaches when evaluating causal effects on injury risk. RESULTS: When a risk factor of interest changes workload, including workload in the regression will cause bias. When workload represents time-at-risk (e.g. games played, minutes run), including workload as an offset in Poisson regression provides a comparison of injury rates (injuries per unit time). This is equivalent to including log(workload) as an independent variable with the coefficient fixed to 1. If workload is included as an independent variable instead of an offset, using log(workload) rather than workload is more consistent with theory. This practice is similar to the principles of allometric scaling. When workload represents a combination of both time-at-risk and intensity, such as with session ratings of perceived exertion, the optimal analytical strategy may require modeling time-at-risk and intensity separately rather than as one factor. CONCLUSIONS: Whether to account for recent workload or not, and how to account for recent workload, depends on the research question and the causal assumptions, both of which should be explicitly stated.

Patient-specific finite element analysis of heart failure and the impact of surgical intervention in pulmonary hypertension secondary to mitral valve disease.

Pulmonary hypertension (PH), a chronic and complex medical condition affecting 1% of the global population, requires clinical evaluation of right ventricular maladaptation patterns under various conditions. A particular challenge for clinicians is a proper quantitative assessment of the right ventricle (RV) owing to its intimate coupling to the left ventricle (LV). We, thus, proposed a patient-specific computational approach to simulate PH caused by left heart disease and its main adverse functional and structural effects on the whole heart. Information obtained from both prospective and retrospective studies of two patients with severe PH, a 72-year-old female and a 61-year-old male, is used to present patient-specific versions of the Living Heart Human Model (LHHM) for the pre-operative and post-operative cardiac surgery. Our findings suggest that before mitral and tricuspid valve repair, the patients were at risk of right ventricular dilatation which may progress to right ventricular failure secondary to their mitral valve disease and left ventricular dysfunction. Our analysis provides detailed evidence that mitral valve replacement and subsequent chamber pressure unloading are associated with a significant decrease in failure risk post-operatively in the context of pulmonary hypertension. In particular, right-sided strain markers, such as tricuspid annular plane systolic excursion (TAPSE) and circumferential and longitudinal strains, indicate a transition from a range representative of disease to within typical values after surgery. Furthermore, the wall stresses across the RV and the interventricular septum showed a notable decrease during the systolic phase after surgery, lessening the drive for further RV maladaptation and significantly reducing the risk of RV failure.

Association between gastroprotective agents and risk of incident interstitial lung disease in systemic sclerosis.

OBJECTIVES: Although interstitial lung disease (ILD) occurs in over half of systemic sclerosis (SSc) patients and represents a leading cause of mortality, there are currently no preventative strategies. We evaluated if gastroprotective agents were associated with a lower incident risk of SSc-ILD. METHODS: An SSc cohort without clinically apparent ILD at baseline was constructed from the Canadian Scleroderma Research Group registry. The primary exposure was any use of gastroprotective agents. Treatment with promotility agents was assessed as a secondary exposure. Time to development of clinically apparent ILD was compared between exposed and unexposed person-time, using a multivariable marginal structural Cox model incorporating inverse probability of treatment weights to address time-varying confounding. RESULTS: In total, 798 subjects met inclusion criteria. At cohort entry, median disease duration was 7.6 (IQR 3.9-15.6) years. During a median 4.4 (IQR 2.6-7.2) years of follow-up, 158 new ILD cases were diagnosed, for a crude incidence of 4.4 (95% CI 3.8-5.1) events per 100 person-years. Most (2085, 73.4%) person-visits were exposed to gastroprotective agents, 579 (20.4%) were exposed to promotility agents, and 554 (19.5%) were exposed to both agents. The marginal structural weighted hazard ratio (HR) for incident ILD related to gastroprotective agents was 0.86 (95% CI 0.52-1.41). When exposure was defined as treatment with promotility agents, the weighted adjusted HR was 0.79 (95% CI: 0.35-1.77). CONCLUSION: In this large retrospective cohort study, we were unable to demonstrate a protective role for gastroprotective and promotility agents in preventing clinically apparent SSc-ILD.

The semiparametric accelerated trend-renewal process for recurrent event data.

Recurrent event data arise in many biomedical longitudinal studies when health-related events can occur repeatedly for each subject during the follow-up time. In this article, we examine the gap times between recurrent events. We propose a new semiparametric accelerated gap time model based on the trend-renewal process which contains trend and renewal components that allow for the intensity function to vary between successive events. We use the Buckley-James imputation approach to deal with censored transformed gap times. The proposed estimators are shown to be consistent and asymptotically normal. Model diagnostic plots of residuals and a method for predicting number of recurrent events given specified covariates and follow-up time are also presented. Simulation studies are conducted to assess finite sample performance of the proposed method. The proposed technique is demonstrated through an application to two real data sets.

Challenges in interpreting results from 'multiple regression' when there is interaction between covariates.

Properly interpreting research results is the foundation of evidence-based medicine. Most observational studies use multiple regression and report adjusted effects. In randomised trials, adjusted effects are often provided when there are chance baseline imbalances. The estimates for the exposure of interest (eg, treatment) from these adjusted analyses are usually interpreted as population average causal effects (PACEs); for example, what would be the difference in the mean outcome if everyone in the population was treated versus untreated? In this paper, we show this interpretation is incorrect when there is an interaction between treatment and other variables with respect to the outcome. We provide the appropriate methods to calculate the PACE from regression analyses and also introduce alternative methods that have gained popularity over the last 20 years. Finally, we explain why researchers should be cautious when excluding interaction terms based on p values.

The Influence of Time of Season on Injury Rates and the Epidemiology of Canadian Football Injuries.

OBJECTIVE: To describe injury rates and injury patterns in the Canadian Football League (CFL) according to time during the season, player position, injury type, and injury location. DESIGN: Prospective, cohort study. SETTING AND PARTICIPANTS: Eight seasons from CFL injury surveillance database. INDEPENDENT VARIABLES: Depending on the analysis, time of season (preseason, regular, and playoffs), player position, injury type, and injury location. MAIN OUTCOME MEASURES: Medical attention and time-loss injury rates per 100 athletes at risk (AAR), and prevalence of time-loss injuries per week. RESULTS: The average game injury rate was 45.2/100 AAR medical attention injuries and 30.7/100 AAR time-loss injuries. Injury rates declined by 1% per week over the season for both medical attention (rate ratio = 0.99) and time-loss (rate ratio = 0.99) injuries, with a substantial decline during the playoffs compared with preseason (rate ratio = 0.70-0.77). The number of ongoing time-loss injuries increased over the course of the regular season. Quarterbacks, offensive backs, and linebackers had the highest game injury rates. Joint/ligament and muscle/tendon injuries were the most common injury types for games and practices, respectively. The lower extremity was the most commonly affected area, specifically the lower leg/ankle/foot and hip/groin/thigh. CONCLUSIONS: There was a 1% decline in injury rate per week during the season and a 30% decline during the playoffs. The number of ongoing time-loss injuries increased over the regular season. Current results can aid league officials and medical staff in making evidence-based decisions concerning player safety and health.

Association between immunosuppressive therapy and course of mild interstitial lung disease in systemic sclerosis.

OBJECTIVE: Interstitial lung disease (ILD) is a leading cause of mortality in SSc. Little is known about the benefits of immunosuppressive drugs in mild ILD. Our aim was to determine whether use of CYC or MMF was associated with an improved ILD course in patients with normal or mildly impaired lung function. METHODS: A retrospective cohort of SSc subjects with ILD, disease duration below seven years and no exposure to CYC or MMF prior to the baseline visit was constructed from the Canadian Scleroderma Research Group registry. Subjects were categorized as having mild ILD if baseline forced vital capacity (FVC % predicted) was >85%. The primary exposure was any use of CYC or MMF at the baseline visit. FVC at one year was compared between exposed and unexposed subjects, using multivariate linear regression. RESULTS: Out of 294 eligible SSc-ILD subjects, 116 met criteria for mild ILD. In this subgroup, mean (s.d.) disease duration was 3.7 (2.0) years. Thirteen (11.2%) subjects were exposed to CYC or MMF at baseline. The one-year FVC was higher in exposed subjects compared with unexposed subjects, by a difference of 8.49% (95% CI: 0.01-16.98%). None of the exposed subjects experienced clinically meaningful progression over two years, whereas 24.6% of unexposed subjects did. CONCLUSION: In this real-world setting, CYC/MMF exposure at baseline was associated with higher FVC values and a lower risk of progression among subjects with mild ILD. These data suggest a window of opportunity to preserve lung function in SSc-ILD.

A randomized controlled trial assessing the efficacy of a self-administered psycho-educational intervention for patients with cancer.

OBJECTIVE: Bibliotherapy refers to psychological self-help interventions that utilize treatment books to improve psychological well-being. Research supports bibliotherapy as an efficacious intervention for a variety of mental health problems. Yet, few studies have investigated bibliotherapy in psychosocial oncology. The objective of this randomized controlled trial was to examine the efficacy of the NuCare intervention, delivered as a self-directed workbook, for enhancing empowerment, coping, and quality of life and reducing distress in patients with cancer. METHODS: Eighty-nine adult patients with cancer were randomized to receive the workbook for 6 weeks or the control condition, usual care. Participants completed questionnaires at baseline, 6 weeks post-baseline, and 10 weeks post-baseline. RESULTS: The increase of empowerment (main outcome) and quality of life and the decrease of distress in the NuCare group from pre-intervention to follow-up assessment differed significantly from the respective difference scores in the control group. CONCLUSIONS: The self-administered NuCare workbook is a potentially cost-effective, minimal intervention addressing psychosocial needs of patients with cancer. PRACTICE IMPLICATIONS: Evidence-based bibliotherapy can empower patients and has the promise of reducing the burden on the healthcare system while enhancing the immediacy of psychosocial support.

Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews.

BACKGROUND: Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. METHOD: Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit. RESULTS: A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98-10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26-0.97). CONCLUSIONS: The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

Synthesizing Risk from Summary Evidence Across Multiple Risk Factors.

Although meta-analyses provide summary effect estimates that help advise patient care, patients often want to compare their overall health to the general population. The Harvard Cancer Risk Index was published in 2004 and uses risk ratio estimates and prevalence estimates from original studies across many risk factors to provide an answer to this question. However, the published version of the formula only uses dichotomous risk factors and its derivation was not provided. The objective of this brief report was to provide the derivation of a more general form of the equation that allows the incorporation of risk factors with three or more levels.