Identifying safe diagnostic algorithms for sentinel lymph node mapping in high-risk endometrial cancer: The SENTIREC-endo study.

INTRODUCTION: It is unclear if sentinel node (SLN) mapping can replace pelvic- (PLD) and paraaortic lymphadenectomy (PALD) for high-risk endometrial cancer (EC). A diagnostically safe surgical algorithm, taking failed mapping cases into account, is not defined. We aimed to investigate the diagnostic accuracy of SLN mapping algorithms in women with exclusively high-risk EC. METHODS: We undertook a prospective national diagnostic cohort study of SLN mapping in women with high-risk EC from March 2017 to January 2023. The power calculation was based on the negative predictive value (NPV). Women underwent SLN mapping, PLD and PALD besides removal of suspicious and any FDG/PET-positive lymph nodes. Accuracy analyses were performed for five algorithms. RESULTS: 170/216 included women underwent SLN mapping, PLD and PALD and were included in accuracy analyses. 42/170 (24.7%) had nodal metastasis. The algorithm SLN and PLD in case of failed mapping, demonstrated a sensitivity of 86% (95% CI 74-100) and an NPV of 96% (95% CI 91-100). The sensitivity increased to 93% (95% CI 83-100) and the NPV to 98% (95% CI 94-100) if PLD was combined with removal of any PET-positive lymph nodes. Equivalent results were obtained if PLD and PALD were performed in non-mapping cases; sensitivity 93% (95% CI 83-100) and NPV 98% (95% CI 95-100). CONCLUSION: SLN-mapping is a safe staging procedure in women with high-risk EC if strictly adhering to a surgical algorithm including removal of any PET-positive lymph nodes independent of location and PLD or PLD and PALD in case of failed mapping.

Fueling the flames of colon cancer - does CRP play a direct pro-inflammatory role?

Background: Systemic inflammation, diagnostically ascribed by measuring serum levels of the acute phase reactant C-reactive protein (CRP), has consistently been correlated with poor outcomes across cancer types. CRP exists in two structurally and functionally distinct isoforms, circulating pentameric CRP (pCRP) and the highly pro-inflammatory monomeric isoform (mCRP). The aim of this pilot study was to map the pattern of mCRP distribution in a previously immunologically well-defined colon cancer (CC) cohort and explore possible functional roles of mCRP within the tumor microenvironment (TME). Methods: Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 43 stage II and III CC patients, including 20 patients with serum CRP 0-1 mg/L and 23 patients with serum CRP >30 mg/L were immunohistochemically (IHC) stained with a conformation-specific mCRP antibody and selected immune and stromal markers. A digital analysis algorithm was developed for evaluating mCRP distribution within the primary tumors and adjacent normal colon mucosa. Results: mCRP was abundantly present within tumors from patients with high serum CRP (>30 mg/L) diagnostically interpreted as being systemically inflamed, whereas patients with CRP 0-1 mg/L exhibited only modest mCRP positivity (median mCRP per area 5.07‰ (95%CI:1.32-6.85) vs. 0.02‰ (95%CI:0.01-0.04), p<0.001). Similarly, tissue-expressed mCRP correlated strongly with circulating pCRP (Spearman correlation 0.81, p<0.001). Importantly, mCRP was detected exclusively within tumors, whereas adjacent normal colon mucosa showed no mCRP expression. Double IHC staining revealed colocalization of mCRP with endothelial cells and neutrophils. Intriguingly, some tumor cells also colocalized with mCRP, suggesting a direct interaction or mCRP expression by the tumor itself. Conclusion: Our data show that the pro-inflammatory mCRP isoform is expressed in the TME of CC, primarily in patients with high systemic pCRP values. This strengthens the hypothesis that CRP might not only be an inflammatory marker but also an active mediator within tumors.

The SENTIREC-endo study - Risks and benefits of a national adoption of sentinel node mapping in low and intermediate risk endometrial cancer.

OBJECTIVE: The SENTIREC-endo study aims to investigate risks and benefits of a national protocolled adoption of sentinel lymph node (SLN) mapping in women with early-stage low-grade endometrial cancer (EC) with low- (LR) and intermediate-risk (IR) of lymph node metastases. METHODS: We performed a national multicenter prospective study of SLN-mapping in women with LR and IR EC from March 2017-February 2022. Postoperative complications were classified according to Clavien-Dindo. Lymphedema was assessed as a change score and as incidence of swelling and heaviness evaluated by validated patient-reported outcome measures at baseline and three months postoperatively. RESULTS: 627 women were included in the analyses; 458 with LR- and 169 with IR EC. The SLN detection rate was 94.3% (591/627). The overall incidence of lymph node metastases was 9.3% (58/627); 4.4% (20/458) in the LR- and 22.5% (38/169) in the IR group. Ultrastaging identified 62% (36/58) of metastases. The incidence of postoperative complications was 8% (50/627) but only 0.3% (2/627) experienced an intraoperative complication associated with the SLN procedure. The lymphedema change score was below the threshold for clinical importance 4.5/100 CI: (2.9-6.0), and the incidence of swelling and heaviness was low; 5.2% and 5.8%, respectively. CONCLUSION: SLN mapping in women with LR and IR EC carries a very low risk of early lymphedema and peri- and postoperative complications. The national change in clinical practice contributed to a more correct treatment allocation for both risk groups and thus supports further international implementation of the SLN technique in early stage, low grade EC.

Interactions Between Running Volume and Running Pace and Injury Occurrence in Recreational Runners: A Secondary Analysis.

CONTEXT: The combination of excessive increases in running pace and volume is essential to consider when investigating associations between running and running-related injury. OBJECTIVES: To complete a secondary analysis, using a dataset from a randomized trial, to evaluate the interactions between relative or absolute weekly changes in running volume and running pace on the occurrence of running injuries among a cohort of injury-free recreational runners in Denmark. DESIGN: Prospective cohort study. SETTING: Running volume and pace were collected during a 24-week follow-up using global positioning systems data. Training data were used to calculate relative and absolute weekly changes in running volume and pace. PATIENTS OR OTHER PARTICIPANTS: A total of 586 recreational runners were included in the analysis. All participants were injury free at baseline. MAIN OUTCOME MEASURE(S): Running-related injury was the outcome. Injury data were collected weekly using a modified version of the Oslo Sports Trauma Research Centre questionnaire. Risk difference (RD) was the measure of injury risk. RESULTS: A total of 133 runners sustained running-related injuries. A relative weekly change of progression >10% in running volume and progression in running pace (RD = 8.1%, 95% CI = -9.3%, 25.6%) and an absolute weekly change of progression >5 km in running volume and progression in running pace (RD = 5.2%, 95% CI = -12.0%, 22.5%) were not associated with a statistically significant positive interaction. CONCLUSIONS: Given that coaches, clinicians, and athletes may agree that excessive increases in running pace and running volume are important contributors to injury development, we analyzed the interaction between them. Although we did not identify a statistically significant positive interaction on an additive scale in runners who progressed both running pace and running volume, readers should be aware that an interaction is an important analytical approach that could be applied to other datasets in future publications.

Systemic Inflammation Associates With a Myeloid Inflamed Tumor Microenvironment in Primary Resected Colon Cancer-May Cold Tumors Simply Be Too Hot?

Systemic inflammation measured by the acute-phase protein CRP associates with poor outcome across cancer types. In contrast, local tumor-associated inflammation, primarily evaluated by T-lymphocytes, correlates with favorable prognosis. Yet, little is known whether these two responses are related or opposing processes and why elevated CRP in relation to cancer is detrimental for clinical outcome. As proof of concept, we developed a platform combining multiplexed IHC and digital imaging, enabling a virtual readout of both lymphoid and myeloid immune markers and their spatial patterns in the primary tumors of resected stage II and III colon cancer (CC) patients with and without accompanying systemic inflammation. Twenty-one patients with elevated CRP (>30 mg/l) and 15 patients with low CRP (<10 mg/l) were included in the analyses. Whole slides from the primary tumors were stained for markers of adaptive (CD8+, CD4+, foxp3 regulatory T cells, CD20+ B cells) and innate (CD68+ macrophages, CD66b+ neutrophils) immunity and the immune checkpoint molecule PD-L1. Associations between individual immune markers, preoperative CRP values, mismatch repair status (MMR), and risk of recurrence or death were assessed. Unsupervised hierarchical clustering was used to explore whether distinct immune phenotypes were present. Tumors from systemically inflamed patients (CRP >30 mg/l) displayed significantly more myeloid features in terms of higher densities of CD66b+neutrophils (p = 0.001) and CD68+macrophages (p = 0.04) and less lymphoid features (lower CD8 T cell, p = 0.03, and foxp3 regulatory T cell densities, p = 0.03) regardless of MMR status. Additionally, systemically inflamed patients harbored lower mean distances between neutrophils and tumor cells within the TME. Intriguingly, microsatellite instable (MSI) tumor status correlated with systemic inflammation. However, using a combinatorial approach, we found that regardless of an adaptive composite score (compounded CD4+ and CD8+ T cells), a high innate score (CD66b+ neutrophils and CD68+ macrophages) associated significantly with elevated CRP. In conclusion, tumor-associated systemic inflammation correlated with a myeloid-dominated TME in a small cohort of resectable CC patients. Our data highlight the importance of a comprehensive immune classification of tumors including players of innate immunity and support a role for CRP as an informative biomarker of the immune response taking place at the tumor site.

Regression models for interval censored data using parametric pseudo-observations.

BACKGROUND: Time-to-event data that is subject to interval censoring is common in the practice of medical research and versatile statistical methods for estimating associations in such settings have been limited. For right censored data, non-parametric pseudo-observations have been proposed as a basis for regression modeling with the possibility to use different association measures. In this article, we propose a method for calculating pseudo-observations for interval censored data. METHODS: We develop an extension of a recently developed set of parametric pseudo-observations based on a spline-based flexible parametric estimator. The inherent competing risk issue with an interval censored event of interest necessitates the use of an illness-death model, and we formulate our method within this framework. To evaluate the empirical properties of the proposed method, we perform a simulation study and calculate pseudo-observations based on our method as well as alternative approaches. We also present an analysis of a real dataset on patients with implantable cardioverter-defibrillators who are monitored for the occurrence of a particular type of device failures by routine follow-up examinations. In this dataset, we have information on exact event times as well as the interval censored data, so we can compare analyses of pseudo-observations based on the interval censored data to those obtained using the non-parametric pseudo-observations for right censored data. RESULTS: Our simulations show that the proposed method for calculating pseudo-observations provides unbiased estimates of the cumulative incidence function as well as associations with exposure variables with appropriate coverage probabilities. The analysis of the real dataset also suggests that our method provides estimates which are in agreement with estimates obtained from the right censored data. CONCLUSIONS: The proposed method for calculating pseudo-observations based on the flexible parametric approach provides a versatile solution to the specific challenges that arise with interval censored data. This solution allows regression modeling using a range of different association measures.

Outcome of hybrid compared to conventional revascularization in multivessel coronary artery disease.

OBJECTIVES: Evaluation of 3-year clinical outcome of hybrid myocardial revascularization (HMR) compared to conventional revascularization strategies in patients with multivessel coronary artery disease involving the proximal left anterior descending artery. Design. Retrospective matched cohort study based on a prospective feasibility study including 103 elective patients undergoing staged HMR from October 2010 until February 2012. The Western Denmark Heart Registry was used to identify patients who underwent coronary artery bypass grafting (CABG) and multivessel percutaneous coronary intervention (PCI) by matching on number of diseased vessels, age and comorbidity score. Primary endpoint was the composite rate of major adverse cardiovascular and cerebrovascular events (MACCE) at 3-year follow-up. Secondary endpoints included individual MACCE components, acute kidney injury, and cardiovascular readmissions. Results. There was no difference between MACCE in the three groups (HMR 31.1%; CABG 20.4%; PCI 20.4%, p = .11). Estimates of repeat revascularization were significantly increased with HMR versus CABG. In the CABG group, fewest patients required cardiovascular readmissions though with the highest incidence of acute kidney injury. Conclusions. HMR was not superior with respect to MACCE compared with CABG and PCI. It may, however, represent a safe alternative to conventional revascularization treatment considering the specific procedure-associated morbidity.

Coffee intake during pregnancy and childhood acute leukemia - A cohort study.

OBJECTIVES: To estimate a possible association between coffee intake during pregnancy and risk of childhood acute leukemia by using a cohort design. METHODS: We included data from two birth cohorts; the Danish National Birth Cohort and the Aarhus Birth Cohort. Recruitment of 141,216 eligible pregnancies occurred from 1 August 1989 to 31 December 2012. Information on maternal prenatal coffee intake and covariates was collected in early second trimester of pregnancy. Information on childhood AL diagnosed in offspring was obtained from the Danish National Patient Register. We used competing risk time-to-event regression analysis, using the pseudo-observation method to estimate risk ratio (RR) with no coffee intake during pregnancy considered the reference group. RESULTS: In total 96 children were diagnosed with AL, hereof 73 with acute lymphoblastic leukemia (ALL). Coffee intake of 0.5-3 cups/day during pregnancy was not associated with a higher risk of childhood AL; aRR = 0.89, 95 % confidence interval (CI): 0.48, 1.65, however, an intake of >3 cups/day resulted in aRR = 1.37, 95 % CI: 0.56, 3.32. Only including ALL as outcome we found similar results; aRR = 0.80, 95 % CI: 0.37-1.74 and aRR = 1.46 95 % CI: 0.52-4.09, respectively. CONCLUSION: We found no significant association between maternal coffee intake and risk of childhood AL but the number of cases was limited. The confidence limits does not exclude that a high prenatal coffee intake may increase the risk of childhood AL and larger studies based on prospective data are needed.

Childhood overweight and obesity and timing of puberty in boys and girls: cohort and sibling-matched analyses.

BACKGROUND: Early puberty is a risk indicator for adult diseases. Identification of modifiable causes of earlier puberty is, therefore, warranted. We estimate the association between childhood body mass index (BMI) and pubertal timing in a cohort study and in a sibling-matched study to adjust for unobserved time-stable confounders shared within families. METHODS: For the cohort study, 11 046 of 22 439 (49%) invited children, born 2000-203, from the Danish National Birth Cohort (DNBC) had information on childhood BMI at 7 years and self-reported, half-yearly puberty information from 11 years on Tanner stages, menarche, voice break, first ejaculation, acne, and axillary hair. For the sibling-matched study, 1700 brothers and sisters were included among 86 820 live-born singletons from the DNBC. RESULTS: Childhood overweight (85th ≤ BMI < 95th percentile) and obesity (BMI ≥ 95th percentile) were associated with earlier age attaining the pubertal milestones in a dose-dependent manner in boys and girls. When modelling all pubertal milestones simultaneously, the pubertal milestones were attained earlier in: overweight boys: -3.1 [95% confidence interval (CI): -4.5, -1.7] months, overweight girls: -5.5 (95% CI: -7.1, -3.9) months, obese boys: -3.5 (95% CI: -5.1, -2.0) months, obese girls: -5.2 (95% CI: -7.1, -3.4) months compared with normal weight (BMI < 85th percentile) children. In the sibling-matched study, higher BMI was associated with earlier age at attaining most pubertal milestones in girls, but only a tendency toward earlier pubertal timing was observed in boys. CONCLUSIONS: Childhood overweight and obesity were associated with earlier pubertal timing even after adjustment for unobserved time-stable confounders shared within families.

Risk of selection bias due to non-participation in a cohort study on pubertal timing.

BACKGROUND: Non-participation in aetiologic studies of pubertal timing is frequent. However, little effort has been given to explore the risk and potential impact of selection bias in studies of pubertal timing. OBJECTIVE: We aimed to explore the risk of selection bias due to non-participation in a newly established puberty cohort. METHODS: We evaluated whether three maternal exposures chosen a priori (pre-pregnancy obesity, smoking, and alcohol drinking during pregnancy) were associated with participation, whether pubertal timing was associated with participation, and whether selection bias influenced the associations between these exposures and pubertal timing. In total, 22 439 children from the Danish National Birth Cohort born 2000-2003 were invited to the Puberty Cohort and 15 819 (70%) participated. Exposures were self-reported during pregnancy. Pubertal timing was measured using a previously validated marker, "the height difference in standard deviations" (HD:SDS), which is the difference between pubertal height and adult height, both in standard deviations. For this study, pubertal height at around 13 years in sons and around 11 years in daughters was obtained from an external database, and adult height was predicted based on parental height reported by mothers. RESULTS: Participation was associated with most exposures but not with pubertal timing, measured by HD:SDS. The associations between exposures and HD:SDS were comparable for participants only and all invited for participation. CONCLUSION: In conclusion, the risk of selection bias in aetiologic studies on pubertal timing in the Puberty Cohort appears minimal.

Methods matter: exploring the 'too much, too soon' theory, part 1: causal questions in sports injury research.

BACKGROUND: It is widely accepted that athletes sustain sports injury if they train 'too much, too soon'. However, not all athletes are built the same; some can tolerate more training than others. It is for this reason that prescribing the same training programme to all athletes to reduce injury risk is not optimal from a coaching perspective. Rather, athletes require individualised training plans. In acknowledgement of athlete diversity, it is therefore essential to ask the right causal research question in studies examining sports injury aetiology. PURPOSE: In this first part of a British Journal of Sports Medicine educational series, we present four different causal research questions related to the 'too much, too soon' theory and critically discuss their relevance to sports injury prevention. CONTENT: If it is true that there is no 'one size fits all' training programme, then we need to consider by how much training can vary depending on individual athlete characteristics. To provide an evidence-base for subgroup-specific recommendations, a stronger emphasis on the following questions is needed: (1) How much training is 'too much' before athletes with different characteristics sustain sports-related injury? and (2) Does the risk of sports injury differ among athletes with a certain characteristic (eg, high experience) compared with athletes with other characteristics (eg, low experience) depending on how much training they perform? CONCLUSION: We recommend that sports injury researchers aiming to examine the 'too much, too soon' theory should carefully consider how they, assisted by coaches, athletes and clinicians, pose their causal research question. In the light of the limitations of population-based prevention that intends to provide all athletes with the same advice, we argue that a stronger emphasis on research questions targeting subgroups of athletes is needed. In doing so, researchers may assist athletes, clinicians and coaches to understand what training advice/programme works best, for whom and under what circumstances.

Maternal pre-pregnancy body mass index, smoking in pregnancy, and alcohol intake in pregnancy in relation to pubertal timing in the children.

BACKGROUND: Earlier pubertal timing has been observed in many countries. We aimed to explore if prenatal exposure to maternal obesity, smoking, and alcohol intake was associated with timing of puberty by use of a novel marker of pubertal timing: 'the height difference in standard deviations' (HD:SDS). METHODS: HD:SDS is the difference between pubertal height in standard deviations and adult height in standard deviations, and it correlates well with age at peak height velocity. Pubertal height was measured by health care professionals at approximately 13 years in boys and 11 years in girls, and the children's adult height was predicted from parental height reported by the mothers during pregnancy. Information on HD:SDS was available for 42,849 of 56,641 eligible boys and girls from the Danish National Birth Cohort born 2000-2003. In a subsample, HD:SDS was validated against age at the following self-reported pubertal milestones: Tanner stages, menarche, first ejaculation, voice break, acne, and axillary hair. Prenatal exposures were reported by mothers during pregnancy. RESULTS: HD:SDS correlated moderately with the pubertal milestones considered (correlation coefficients: - 0.20 to - 0.53). With normal weight (body mass index (BMI): 18.5-24.9 kg/m2) as the reference, maternal pre-pregnancy obesity (BMI: 30.0+ kg/m2) was associated with earlier pubertal timing: 0.23 (95% confidence interval (CI): 0.18, 0.28) higher HD:SDS in boys and 0.19 (95% CI, 0.14, 0.24) higher HD:SDS in girls. Maternal smoking was not associated with pubertal timing. Compared to alcohol abstainers, maternal intake of > 3 units of alcohol weekly was associated with later puberty in boys only: 0.14 (95% CI, 0.05, 0.24) lower HD:SDS. CONCLUSION: As correlations between HD:SDS and the considered pubertal milestones were comparable to those reported in the literature between age a peak height velocity and the considered pubertal milestones, the validity of HD:SDS seems acceptable. Maternal pre-pregnancy obesity was associated with earlier pubertal timing in both sexes, and maternal alcohol intake during pregnancy was associated with later pubertal timing in boys. Maternal smoking has been linked to earlier timing of puberty, but this was not replicated in our setting using HD:SDS as a marker of pubertal timing.

The Garmin-RUNSAFE Running Health Study on the aetiology of running-related injuries: rationale and design of an 18-month prospective cohort study including runners worldwide.

INTRODUCTION: Running injuries affect millions of persons every year and have become a substantial public health issue owing to the popularity of running. To ensure adherence to running, it is important to prevent injuries and to have an in-depth understanding of the aetiology of running injuries. The main purpose of the present paper was to describe the design of a future prospective cohort study exploring if a dose-response relationship exists between changes in training load and running injury occurrence, and how this association is modified by other variables. METHODS AND ANALYSIS: In this protocol, the design of an 18-month observational prospective cohort study is described that will include a minimum of 20 000 consenting runners who upload their running data to Garmin Connect and volunteer to be a part of the study. The primary outcome is running-related injuries categorised into the following states: (1) no injury; (2) a problem; and (3) injury. The primary exposure is change in training load (eg, running distance and the cumulative training load based on the number of strides, ground contact time, vertical oscillation and body weight). The change in training load is a time-dependent exposure in the sense that progression or regression can change many times during follow-up. Effect-measure modifiers include, but is not limited to, other types of sports activity, activity of daily living and demographics, and are assessed through questionnaires and/or by Garmin devices. ETHICS AND DISSEMINATION: The study design, procedures and informed consent have been evaluated by the Ethics Committee of the Central Denmark Region (Request number: 227/2016 - Record number: 1-10-72-189-16).

ProjectRun21: Do running experience and running pace influence the risk of running injury-A 14-week prospective cohort study.

OBJECTIVES: The health benefits from participation in half-marathon is challenged by a yearly running-related injury (RRI) incidence proportion exceeding 30%. Research in injury etiology is needed to successfully prevent injuries. The body's load capacity is believed to play an essential role for injury development. Therefore, the purpose of ProjectRun21 was to investigate the association between load capacity defined as running experience and running pace, and RRI when following a specific half-marathon running schedule. DESIGN: A 14-week prospective cohort study. METHODS: A cohort of 784 healthy runners followed a specific half-marathon running schedule. Data on running activity was collected objectively using a Global-Positioning-System watch or smartphone. RRI were collected using e-mail-based weekly questionnaires. Primary exposures were running experience and running pace, dichotomized into a high and a low group for runners running less or more than 15km/week and faster or slower than 6min/km, respectively. Data was analyses through time-to-event models with cumulative risk difference (RD) as measure of association. RESULTS: A total of 136 participants sustained a RRI during follow-up. Although not statistically significant, all estimates indicate a tendency toward fewer injuries amongst runners categorized as having high experience (RD=-11.3% (-27.2% to 4.6%)) or high pace (RD=-17.4% (-39.0% to 4.5%)), and a combination of both high experience and high pace (RD=-8.1% (-22.3% to 6.1%)) compared with their counterpart peers. CONCLUSIONS: Runners covering less than 15km per week, and/or runs slower than 6min/km, may sustain more RRI than their counterpart runners.

Time-to-event analysis for sports injury research part 1: time-varying exposures.

BACKGROUND: 'How much change in training load is too much before injury is sustained, among different athletes?' is a key question in sports medicine and sports science. To address this question the investigator/practitioner must analyse exposure variables that change over time, such as change in training load. Very few studies have included time-varying exposures (eg, training load) and time-varying effect-measure modifiers (eg, previous injury, biomechanics, sleep/stress) when studying sports injury aetiology. AIM: To discuss advanced statistical methods suitable for the complex analysis of time-varying exposures such as changes in training load and injury-related outcomes. CONTENT: Time-varying exposures and time-varying effect-measure modifiers can be used in time-to-event models to investigate sport injury aetiology. We address four key-questions (i) Does time-to-event modelling allow change in training load to be included as a time-varying exposure for sport injury development? (ii) Why is time-to-event analysis superior to other analytical concepts when analysing training-load related data that changes status over time? (iii) How can researchers include change in training load in a time-to-event analysis? and, (iv) Are researchers able to include other time-varying variables into time-to-event analyses? We emphasise that cleaning datasets, setting up the data, performing analyses with time-varying variables and interpreting the results is time-consuming, and requires dedication. It may need you to ask for assistance from methodological peers as the analytical approaches presented this paper require specialist knowledge and well-honed statistical skills. CONCLUSION: To increase knowledge about the association between changes in training load and injury, we encourage sports injury researchers to collaborate with statisticians and/or methodological epidemiologists to carefully consider applying time-to-event models to prospective sports injury data. This will ensure appropriate interpretation of time-to-event data.

Time-to-event analysis for sports injury research part 2: time-varying outcomes.

BACKGROUND: Time-to-event modelling is underutilised in sports injury research. Still, sports injury researchers have been encouraged to consider time-to-event analyses as a powerful alternative to other statistical methods. Therefore, it is important to shed light on statistical approaches suitable for analysing training load related key-questions within the sports injury domain. CONTENT: In the present article, we illuminate: (i) the possibilities of including time-varying outcomes in time-to-event analyses, (ii) how to deal with a situation where different types of sports injuries are included in the analyses (ie, competing risks), and (iii) how to deal with the situation where multiple subsequent injuries occur in the same athlete. CONCLUSION: Time-to-event analyses can handle time-varying outcomes, competing risk and multiple subsequent injuries. Although powerful, time-to-event has important requirements: researchers are encouraged to carefully consider prior to any data collection that five injuries per exposure state or transition is needed to avoid conducting statistical analyses on time-to-event data leading to biased results. This requirement becomes particularly difficult to accommodate when a stratified analysis is required as the number of variables increases exponentially for each additional strata included. In future sports injury research, we need stratified analyses if the target of our research is to respond to the question: 'how much change in training load is too much before injury is sustained, among athletes with different characteristics?' Responding to this question using multiple time-varying exposures (and outcomes) requires millions of injuries. This should not be a barrier for future research, but collaborations across borders to collecting the amount of data needed seems to be an important step forward.

The Association Between Changes in Weekly Running Distance and Running-Related Injury: Preparing for a Half Marathon.

BACKGROUND: Sudden changes in training load may play a key role in the development of running-related injury (RRI). Because the injury mechanism depends on the runner's musculoskeletal load capacity, the running schedule followed prior to sudden change in training load may influence the amount of change that a runner can tolerate before the runner is at a higher risk of RRI. OBJECTIVES: To investigate the association between change in weekly running distance and RRI, and to examine whether the association may be modified by the running schedule the runner follows. METHODS: Two hundred sixty-one healthy (noninjured) runners were included in this prospective cohort study over a period of 14 weeks. Data on running activity were collected daily and objectively, using a global positioning system watch or smartphone. Instances of RRIs were collected using weekly e-mailed questionnaires. Primary exposure was defined as changes in weekly running distance. Data were analyzed with time-to-event models that produced cumulative risk difference as the measure of association. RESULTS: A total of 56 participants (21.5%) sustained an RRI during the 14-week study period. Twenty-one days into the study period, significantly more runners were injured when they increased their weekly running distance by 20% to 60% compared with those who increased their distance by less than 20% (risk difference, 22.6%; 95% confidence interval: 0.9%, 44.3%; P = .041). No significant difference was found after 56 and 98 days. No significant effect-measure modification by running schedule was found. CONCLUSION: Significantly more runners were injured 21 days into the study period when they increased their weekly running distances by 20% to 60% compared with those who increased their distances by less than 20%. LEVEL OF EVIDENCE: Prognosis, level 1b. J Orthop Sports Phys Ther 2019;49(4):230-238. Epub 7 Dec 2018. doi:10.2519/jospt.2019.8541.

Early treatment with talk therapy or antidepressants in severely bereaved people and risk of suicidal behavior and psychiatric illness: an instrumental variable analysis.

PURPOSE: Losing a loved one to death is a common and natural life-course experience. Still, bereavement has been associated with an increased risk of suicidal behavior and psychiatric hospitalization and little is known of how to counter these adverse events. We aimed to study the effect of early treatment in primary care with talk therapy (TT) or antidepressants (AD) in severely bereaved people. METHODS: We conducted a population-based cohort study including 207,435 adult Danes who experienced a severe loss in 1996-2013. We compared treatment and no treatment with either of the two treatment regimens within 6 months after the loss. The main outcome was a serious mental health condition (defined as suicide, deliberate self-harm, or psychiatric hospitalization) occurring >6 months after bereavement. Adjusted risk differences (RDs) 2 years after bereavement were calculated using both standard regression analysis and instrumental variable analysis (IVA) in which estimated physician preferences for treatment served as instruments. RESULTS: The standard adjusted regression analysis showed a higher risk of developing a serious mental health condition associated with both TT (RD, 7.1; 95% CI, 5.0 to 9.1 per 1000 people) and AD (RD, 30.1; 95% CI, 25.7 to 34.6 per 1000 people). The IVA, which was used to control for unmeasured confounding, showed that TT was associated with a lower risk of a serious mental health condition (RD, -17.1; 95% CI, -30.7 to -3.5 per 1000 people), whereas the results were inconclusive for AD (RD, -8.6; 95% CI, -62.6 to 45.4 per 1000 people). CONCLUSION: This study suggests that early treatment with TT is associated with reduced long-term risk of serious mental health conditions in severely bereaved people. No clear benefit or harm of treatment with AD after bereavement was ascertained since the statistical precision was low.