Modeling the Risk of Team Sport Injuries: A Narrative Review of Different Statistical Approaches

Injuries are a common occurrence in team sports and can have significant financial, physical and psychological consequences for athletes and their sporting organizations. As such, an abundance of research has attempted to identify factors associated with the risk of injury, which is important when developing injury prevention and risk mitigation strategies. There are a number of methods that can be used to identify injury risk factors. However, difficulty in understanding the nuances between different statistical approaches can lead to incorrect inferences and decisions being made from data. Accordingly, this narrative review aims to (1) outline commonly implemented methods for determining injury risk, (2) highlight the differences between association and prediction as it relates to injury and (3) describe advances in statistical modeling and the current evidence relating to predicting injuries in sport. Based on the points that are discussed throughout this narrative review, both researchers and practitioners alike need to carefully consider the different types of variables that are examined in relation to injury risk and how the analyses pertaining to these different variables are interpreted. There are a number of other important considerations when modeling the risk of injury, such as the method of data transformation, model validation and performance assessment. With these technical considerations in mind, researchers and practitioners should consider shifting their perspective of injury etiology from one of reductionism to one of complexity. Concurrently, research implementing reductionist approaches should be used to inform and implement complex approaches to identifying injury risk. However, the ability to capture large injury numbers is a current limitation of sports injury research and there has been a call to make data available to researchers, so that analyses and results can be replicated and verified. Collaborative efforts such as this will help prevent incorrect inferences being made from spurious data and will assist in developing interventions that are underpinned by sound scientific rationale. Such efforts will be a step in the right direction of improving the ability to identify injury risk, which in turn will help improve risk mitigation and ultimately the prevention of injuries

Session availability as a result of prior injury impacts the risk of subsequent injury in elite male Australian footballers

Prior injury is a commonly identified risk factor for subsequent injury. However, a binary approach to classifying prior injury (i.e., yes/no) is commonly implemented and may constrain scientific findings, as it is possible that variations in the amount of time lost due to an injury will impact subsequent injury risk to differing degrees. Accordingly, this study investigated whether session availability, a surrogate marker of prior injury, influenced the risk of subsequent non-contact lower limb injury in Australian footballers. Data were collected from 62 male elite Australian footballers throughout the 2015, 2016, and 2017 Australian Football League seasons. Each athlete’s participation status (i.e., full or missed/modified) and any injuries that occurred during training sessions/matches were recorded. As the focus of the current study was prior injury, any training sessions/matches that were missed due to reasons other than an injury (e.g., load management, illness and personal reasons) were removed from the data prior to all analyses. For every Monday during the in-season periods, session availability (%) in the prior 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84 days was determined as the number of training sessions/matches fully completed (injury free) relative to the number of training sessions/matches possible in each window. Each variable was modeled using logistic regression to determine its impact on subsequent injury risk. Throughout the study period, 173 non-contact lower limb injuries that resulted in at least one missed/modified training session or match during the in-season periods occurred. Greater availability in the prior 7 days increased injury probabilities by up to 4.4%. The impact of session availability on subsequent injury risk diminished with expanding windows (i.e., availability in the prior 14 days through to the prior 84 days). Lesser availability in the prior 84 days increased injury probabilities by up to 14.1%, only when coupled with greater availability in the prior 7 days. Session availability may provide an informative marker of the impact of prior injury on subsequent injury risk and can be used by coaches and clinicians to guide the progression of training, particularly for athletes that are returning from long periods of injury

The dose-response of the nordic hamstring exercise on biceps femoris architecture and eccentric knee flexor strength : A randomized interventional trial

Purpose: To examine the dose–response of the Nordic hamstring exercise (NHE) on biceps femoris long head (BFlh) architecture and eccentric knee flexor strength. Design: Randomized interventional trial. Methods: Forty recreationally active males completed a 6-week NHE training program consisting of either intermittent low volumes (group 1; n = 10), low volumes (group 2; n = 10), initial high volumes followed by low volumes (group 3; n = 10), or progressively increasing volumes (group 4; n = 10). A 4-week detraining period followed each program. Muscle architecture was assessed weekly during training and after 2 and 4 weeks of detraining. Eccentric knee flexor strength was assessed preintervention and postintervention and after 2 and 4 weeks of detraining. Results: Following 6 weeks of training, BFlh fascicle length (FL) increased in group 3 (mean difference = 0.83 cm, d = 0.45, P = .027, +7%) and group 4 (mean difference = 1.48 cm, d = 0.94, P = .004, +14%). FL returned to baseline following detraining in groups 3 and 4. Strength increased in group 2 (mean difference = 53.6 N, d = 0.55, P = .002, +14%), group 3 (mean difference = 63.4 N, d = 0.72, P = .027, +17%), and group 4 (mean difference = 74.7, d = 0.83, P = .006, +19%) following training. Strength returned to baseline following detraining in groups 2 and 3 but not in group 4. Conclusions: Initial high volumes of the NHE followed by lower volumes, as well as progressively increasing volumes, can elicit increases in BFlh FL and eccentric knee flexor strength. Low volumes of the NHE were insufficient to increase FL, although as few as 48 repetitions in 6 weeks did increase strength

Linking Power Doppler Ultrasound to the Presence of Th17 Cells in the Rheumatoid Arthritis Joint

Power Doppler ultrasound (PDUS) is increasingly used to assess synovitis in Rheumatoid Arthritis (RA). Prior studies have shown correlations between PDUS scores and vessel counts, but relationships with T cell immunopathology have not been described.PBMC were isolated from healthy controls (HC) or RA patients and stimulated ex vivo with PMA and ionomycin for 3 hours in the presence of Golgistop. Paired synovial fluid (SF) or synovial tissue (ST) were analysed where available. Intracellular expression of IL-17, IFNgamma, and TNFalpha by CD4+ T cells was determined by flow cytometry. Synovial blood flow was evaluated by PDUS signal at the knees, wrists and metacarpophalangeal joints of RA patients. Serum, SF and fibroblast culture supernatant levels of vascular endothelial growth factor-A (VEGF-A) were measured by ELISA. The frequency of IL17+IFNgamma-CD4+ T cells (Th17 cells) was significantly elevated in peripheral blood (PB) from RA patients vs. HC (median (IQR) 0.5 (0.28-1.59)% vs. 0.32 (0.21-0.54)%, p = 0.005). Th17 cells were further enriched (mean 6.6-fold increase) in RA SF relative to RA PB. Patients with active disease had a higher percentage of IL-17+ T cells in ST than patients in remission, suggesting a possible role for Th17 cells in active synovitis in RA. Indeed, the percentage of Th17 cells, but not Th1, in SF positively correlated with CRP (r = 0.51, p = 0.04) and local PDUS-defined synovitis (r = 0.61, p = 0.002). Furthermore, patients with high levels of IL-17+CD4+ T cells in SF had increased levels of the angiogenic factor VEGF-A in SF. Finally, IL-17, but not IFNgamma, increased VEGF-A production by RA synovial fibroblasts in vitro.Our data demonstrate a link between the presence of pro-inflammatory Th17 cells in SF and local PDUS scores, and offer a novel immunological explanation for the observation that rapid joint damage progression occurs in patients with persistent positive PDUS signal

E-cadherin breast tumor expression, risk factors and survival : Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium

E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, > 2 cm, and HER2-negative. Loss of E-cadherin expression (score <100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.Peer reviewe

Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10–8 as genome-wide significant, and p-values < 1 × 10–5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10–7), which showed genome-wide significant interaction (p-value = 3.8 × 10–8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen–progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association

Interferon Regulatory Factor 8 Regulates Pathways for Antigen Presentation in Myeloid Cells and during Tuberculosis

IRF8 (Interferon Regulatory Factor 8) plays an important role in defenses against intracellular pathogens, including several aspects of myeloid cells function. It is required for ontogeny and maturation of macrophages and dendritic cells, for activation of anti-microbial defenses, and for production of the Th1-polarizing cytokine interleukin-12 (IL-12) in response to interferon gamma (IFNγ) and protection against infection with Mycobacterium tuberculosis. The transcriptional programs and cellular pathways that are regulated by IRF8 in response to IFNγ and that are important for defenses against M. tuberculosis are poorly understood. These were investigated by transcript profiling and chromatin immunoprecipitation on microarrays (ChIP-chip). Studies in primary macrophages identified 368 genes that are regulated by IRF8 in response to IFNγ/CpG and that behave as stably segregating expression signatures (eQTLs) in F2 mice fixed for a wild-type or mutant allele at IRF8. A total of 319 IRF8 binding sites were identified on promoters genome-wide (ChIP-chip) in macrophages treated with IFNγ/CpG, defining a functional G/AGAAnTGAAA motif. An analysis of the genes bearing a functional IRF8 binding site, and showing regulation by IFNγ/CpG in macrophages and/or in M. tuberculosis-infected lungs, revealed a striking enrichment for the pathways of antigen processing and presentation, including multiple structural and enzymatic components of the Class I and Class II MHC (major histocompatibility complex) antigen presentation machinery. Also significantly enriched as IRF8 targets are the group of endomembrane- and phagosome-associated small GTPases of the IRG (immunity-related GTPases) and GBP (guanylate binding proteins) families. These results identify IRF8 as a key regulator of early response pathways in myeloid cells, including phagosome maturation, antigen processing, and antigen presentation by myeloid cells

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio