Predicting Injury Risk Over Changes in Physical Activity in Children Using the Acute:Chronic Workload Ratio.

Limited research exists on the relationship between changes in physical activity levels and injury in children. In this study, we investigated the prognostic relationship between changes in activity, measured by the acute:chronic workload ratio (ACWR), and injury in children. We used data from the Childhood Health, Activity, and Motor Performance School Study Denmark (2008-2014), a prospective cohort study of 1,660 children aged 6-17 years. We modeled the relationship between the uncoupled 5-week ACWR and injury, defined as patient-reported musculoskeletal pain, using generalized additive mixed models. These methods accounted for repeated measures, and they improved model fit and precision compared with previous studies that used logistic models. The prognostic model predicted an injury risk of approximately 3% between decreases in activity level of up to 60% and increases of up to 30%. Predicted risk was lower when activity decreased by more than 60% (minimum of 0.5% with no recreational activity). Predicted risk was higher when activity increased by more than 30% (4.5% with a 3-fold increase in activity). Girls were at significantly higher risk of injury than boys. We observed similar patterns but lower absolute risks when we restricted the outcome to clinician-diagnosed injury. Predicted increases in injury risk with increasing activity were much lower than those of previous studies carried out in adults.

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.

Effect of preschool childcare on school-aged children's adiposity in Quebec, Canada.

BACKGROUND: Regulated public childcare must follow nutrition and physical activity guidelines, but the impact of public childcare on childhood adiposity is unclear. OBJECTIVES: To estimate the effects of universal preschool childcare on children's BMI in elementary school in Quebec, Canada, and whether the effects differed in children from more or less advantaged families. METHODS: For 1657 children enrolled in the Quebec Longitudinal Study of Child Development (1998-2010), BMI z-scores (BMIz) from 6 to 13 years were regressed on the childcare used from 2 to 5 years, adjusted for pre-childcare variables. Average treatment effects were estimated using the Bayesian multilevel linear regression and g-computation for four childcare profiles: 1) parental care or full-time care (35 hours/week) in a 2) centre-based, 3) regulated home-based or 4) unregulated home-based arrangement. RESULTS: Had all participants attended centre-based care, mean BMIz in kindergarten would have been 0.38 (95% credible interval [CrI] 0.23, 0.52), which was 0.40 (95% CrI 0.14, 0.65) SD higher than regulated home-based, 0.20 (95% CrI -0.04, 0.43) SD higher than unregulated home-based and 0.36 (95% CrI 0.11, 0.60) SD higher than parental care. By 12 years, mean BMIz had increased for all childcare profiles, but differences between childcare profiles had diminished. CONCLUSIONS: Although centre-based childcare was associated with an earlier rise in BMI, compared with informal care, it had no large, enduring effect, overall, or for less advantaged children, in particular.

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.

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.

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.

Doubly robust estimation and causal inference for recurrent event data.

Many longitudinal databases record the occurrence of recurrent events over time. In this article, we propose a new method to estimate the average causal effect of a binary treatment for recurrent event data in the presence of confounders. We propose a doubly robust semiparametric estimator based on a weighted version of the Nelson-Aalen estimator and a conditional regression estimator under an assumed semiparametric multiplicative rate model for recurrent event data. We show that the proposed doubly robust estimator is consistent and asymptotically normal. In addition, a model diagnostic plot of residuals is presented to assess the adequacy of our proposed semiparametric model. We then evaluate the finite sample behavior of the proposed estimators under a number of simulation scenarios. Finally, we illustrate the proposed methodology via a database of circus artist injuries.

Meta-analysis of the difference of medians.

We consider the problem of meta-analyzing two-group studies that report the median of the outcome. Often, these studies are excluded from meta-analysis because there are no well-established statistical methods to pool the difference of medians. To include these studies in meta-analysis, several authors have recently proposed methods to estimate the sample mean and standard deviation from the median, sample size, and several commonly reported measures of spread. Researchers frequently apply these methods to estimate the difference of means and its variance for each primary study and pool the difference of means using inverse variance weighting. In this work, we develop several methods to directly meta-analyze the difference of medians. We conduct a simulation study evaluating the performance of the proposed median-based methods and the competing transformation-based methods. The simulation results show that the median-based methods outperform the transformation-based methods when meta-analyzing studies that report the median of the outcome, especially when the outcome is skewed. Moreover, we illustrate the various methods on a real-life data set.

One-sample aggregate data meta-analysis of medians.

An aggregate data meta-analysis is a statistical method that pools the summary statistics of several selected studies to estimate the outcome of interest. When considering a continuous outcome, typically each study must report the same measure of the outcome variable and its spread (eg, the sample mean and its standard error). However, some studies may instead report the median along with various measures of spread. Recently, the task of incorporating medians in meta-analysis has been achieved by estimating the sample mean and its standard error from each study that reports a median in order to meta-analyze the means. In this paper, we propose two alternative approaches to meta-analyze data that instead rely on medians. We systematically compare these approaches via simulation study to each other and to methods that transform the study-specific medians and spread into sample means and their standard errors. We demonstrate that the proposed median-based approaches perform better than the transformation-based approaches, especially when applied to skewed data and data with high inter-study variance. Finally, we illustrate these approaches in a meta-analysis of patient delay in tuberculosis diagnosis.

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.

Estimating Causal Effects of Treatment in a Randomized Trial When Some Participants Only Partially Adhere.

The intention-to-treat analysis evaluates the causal effect of treatment assignment in a randomized controlled trial; however, participants do not always adhere to assigned treatment and the intention-to-treat effect may differ from the effect of treatment receipt. Although more recent adherence-based methods assess a well-defined causal effect of receiving treatment, adherence is assumed to be dichotomized as all or none. This approach can lack precision in the real world because adherence is a complex and heterogeneous phenomenon. In this article, we illustrate a simple method that provides estimates of bounds on the causal effect of full adherence to treatment in the presence of partial adherence. We first define three types of partial adherence (delayed, partial-dose, posttreatment). We then use casual diagrams to show that categorizing partial adherence as nonadherence in a sensitivity analysis can lead to a violation of the exclusion restriction principle. Finally, we apply recently published sensitivity analyses related to principal stratification that allow for creating bound estimates around the causal effect of treatment in the presence of partial adherence.

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.

Selective Cutoff Reporting in Studies of Diagnostic Test Accuracy: A Comparison of Conventional and Individual-Patient-Data Meta-Analyses of the Patient Health Questionnaire-9 Depression Screening Tool.

In studies of diagnostic test accuracy, authors sometimes report results only for a range of cutoff points around data-driven "optimal" cutoffs. We assessed selective cutoff reporting in studies of the diagnostic accuracy of the Patient Health Questionnaire-9 (PHQ-9) depression screening tool. We compared conventional meta-analysis of published results only with individual-patient-data meta-analysis of results derived from all cutoff points, using data from 13 of 16 studies published during 2004-2009 that were included in a published conventional meta-analysis. For the "standard" PHQ-9 cutoff of 10, accuracy results had been published by 11 of the studies. For all other relevant cutoffs, 3-6 studies published accuracy results. For all cutoffs examined, specificity estimates in conventional and individual-patient-data meta-analyses were within 1% of each other. Sensitivity estimates were similar for the cutoff of 10 but differed by 5%-15% for other cutoffs. In samples where the PHQ-9 was poorly sensitive at the standard cutoff, authors tended to report results for lower cutoffs that yielded optimal results. When the PHQ-9 was highly sensitive, authors more often reported results for higher cutoffs. Consequently, in the conventional meta-analysis, sensitivity increased as cutoff severity increased across part of the cutoff range-an impossibility if all data are analyzed. In sum, selective reporting by primary study authors of only results from cutoffs that perform well in their study can bias accuracy estimates in meta-analyses of published results.

A higher sport-related reinjury risk does not mean inadequate rehabilitation: the methodological challenge of choosing the correct comparison group.

Previous injury is a well-established predictor of subsequent injury in sports medicine. Some have interpreted this to mean that either our current methods of rehabilitation are inadequate or there is some permanent damage to the tissue and 100% rehabilitation is not possible. In 2011, we illustrated that these analyses and interpretations failed to account for the fact that some athletes are more prone to get injured, either physiologically, or because of their role/type of play. We suggested that the appropriate analysis would simply require using statistical methods that measured how each individual athlete's risk changed from preinjury to postinjury.In this paper, we revisit our recommendation and illustrate that it too would be flawed if the risk of injury changed over time independent of an injury ever occurring. This might be expected if general fitness were to decline over the season, or if the style of play changed between early season games and postseason championship games. Acknowledging that risk may change regardless of whether an injury occurred or not leads to three different general definitions of 100% rehabilitation: (1) a return to the baseline state, (2) a return to the immediate preinjury state and (3) a return to the state that would have been present had the initial injury never occurred. We guide the reader on how to estimate the risks for each definition and the assumptions that must be acknowledged.

Hospitalizations in Immigrants and Nonimmigrants Diagnosed With Chronic Hepatitis C Infection in Québec.

BACKGROUND: Rates of hospitalization due to chronic hepatitis C virus (HCV) are increasing in Canada and the United States. A large proportion of immigrants originate from countries with intermediate to high HCV prevalence but are not screened for HCV post-arrival and may therefore have increased risks of liver-related complications and hospitalization. METHODS: We conducted a retrospective cohort study of reported HCV cases in Québec, Canada, from 1998 to 2007 that were linked to administrative health databases. Outcomes included all-cause and liver-related hospitalizations and in-hospital days in immigrants compared with nonimmigrants adjusted for age, sex, and comorbidities. RESULTS: We identified 20 139 HCV cases; 9% (N = 1821) were immigrants. At diagnosis, immigrants were older (47.6 vs 43.2 years) and more likely to have hepatocellular carcinoma (HCC; 0.93% vs 0.31%), while nonimmigrants were 2- to 10-fold more likely to have substance use-related comorbidities. Mean time to HCV diagnosis after arrival was 9.8 years. Nonimmigrants had higher rates of all-cause hospitalization (adjusted rate ratio [95% confidence interval], 1.42 [1.35-1.47]), driven by mental illness and injury and/or poisoning. Unadjusted liver-related hospitalization rates were similar between cohorts. After adjustment, immigrant status was associated with lower rates of liver-related hospitalization (0.68 [.53-.88]). CONCLUSIONS: Higher burden of all-cause hospitalization in nonimmigrants likely reflects more prevalent behavioral comorbidities. Similar liver-related hospitalization rates appear to be driven by older age in immigrants who were more likely to have HCC at diagnosis possibly reflecting delayed HCV diagnosis. These findings suggest that earlier screening and treatment in immigrants could play an important role in preventing HCV complications in this population.

Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson's disease.

AIM: Domperidone is preferentially used over other antiemetic agents to treat digestive symptoms in Parkinson's disease (PD). Concerns have been raised regarding an increased risk of ventricular tachyarrhythmia and sudden cardiac death (VT/SCD) associated with domperidone in the general population. However, the risk in PD is unknown. METHODS: We conducted a multicentre retrospective cohort study using administrative databases from seven Canadian provinces and the UK Clinical Practice Research Datalink. Using a nested case-control analysis, we estimated the rate ratios (RRs) of VT/SCD associated with domperidone use compared to no use in patients newly-diagnosed with PD. VT/SCD events were identified using administrative medical records and vital statistics with a manual review of all potential cases. Meta-analytic methods were used to estimate overall effects across sites. RESULTS: Among 214 962 patients with PD, 2907 cases of VT/SCD were identified during 886 581 person-years of follow-up (incidence rate 3.28 per 1000 persons per year). Current use of domperidone was associated with a non-statistically significant 22% increased risk of VT/SCD (RR 1.22; 95% CI 0.99-1.50) compared with no use. The risk was significantly elevated in those with a history of cardiovascular disease (RR 1.38; 95% CI 1.07-1.78), but not in those without (RR 1.21; 95% CI 0.81-1.81). Dose and duration of use did not affect the magnitude of the risk. CONCLUSION: Domperidone use may increase the risk of VT/SCD in patients with PD, particularly those with a history of cardiovascular disease. This risk may be underestimated because of imprecision in identifying VT/SCD events.

Simple Estimation of Patient-Oriented Effects From Randomized Trials: An Open and Shut CACE.

In randomized controlled trials, the intention-to-treat estimator provides an unbiased estimate of the causal effect of treatment assignment on the outcome. However, patients often want to know what the effect would be if they were to take the treatment as prescribed (the patient-oriented effect), and several researchers have suggested that the more relevant causal effect for this question is the complier average causal effect (CACE), also referred to as the local average treatment effect. Sophisticated approaches to estimating the CACE include Bayesian and frequentist methods for principal stratification, inverse-probability-of-treatment-weighted estimators, and instrumental-variable (IV) analysis. All of these approaches exploit information about adherence to assigned treatment to improve upon the intention-to-treat estimator, but they are rarely used in practice, probably because of their complexity. The IV principal stratification estimator is simple to implement but has had limited use in practice, possibly due to lack of familiarity. Here, we show that the IV principal stratification estimator is a modified per-protocol estimator that should be obtainable from any randomized controlled trial, and we provide a closed form for its robust variance (and its uncertainty). Finally, we illustrate sensitivity analyses we conducted to assess inference in light of potential violations of the exclusion restriction assumption.

The Canadian systemic sclerosis oral health study II: the relationship between oral and global health-related quality of life in systemic sclerosis.

OBJECTIVE: Both oral and global health-related quality of life (HRQoL) are markedly impaired in SSc. In this study we aimed to determine the degree of association between oral HRQoL and global HRQoL in SSc. METHODS: Subjects were recruited from the Canadian Scleroderma Research Group registry. Global HRQoL was measured using the Medical Outcomes Trust 36-item Short Form Health Survey (SF-36) and oral HRQoL with the Oral Health Impact Profile (OHIP). The Medsger Disease Severity Score was used to determine organ involvement. Multivariate regression models determined the independent association of the OHIP with the SF-36 after adjusting for confounders. RESULTS: This study included 156 SSc subjects. The majority (90%) were women, with a mean age of 56 years, mean disease duration 13.8 years (s.d. 8.5) and 29% of the subjects had dcSSc. Mean total OHIP score was 40.8 (s.d. 32.4). Mean SF-36 mental component summary (MCS) score was 49.7 (s.d. 11.1) and physical component summary (PCS) score was 37.0 (s.d. 10.7). In adjusted analyses, the total OHIP score was significantly associated with the SF-36 MCS and PCS, accounting for 9.7% and 5.6% of their respective variances. Measures of disease severity were not related to OHIP score. CONCLUSION: Oral HRQoL in SSc is independently associated with global HRQoL. Oral HRQoL, however, is not related to physician-assessed disease severity. This suggests that physicians may be disregarding issues related to oral health. HRQoL is an additional dimension of HRQoL not captured by generic instruments such as the SF-36.