Predictors of low and very low bone mineral density in long-term childhood acute lymphoblastic leukemia survivors: Toward personalized risk prediction.

BACKGROUND: Cohorts of childhood acute lymphoblastic leukemia (cALL) survivors reaching adulthood are increasing. Approximately 30% of survivors meet criteria for low bone mineral density (BMD) 10 years after diagnosis. We investigated risk factors for low BMD in long-term cALL survivors. METHODS: We recruited 245 cALL survivors from the PETALE (Prévenir les effets tardifs des traitements de la leucémie aiguë lymphoblastique chez l'enfant) cohort, who were treated with the Dana Farber Cancer Institute protocols, did not experience disease relapse or hematopoietic stem cell transplants, and presented with more than 5 years of event-free survival. Median time since diagnosis was 15.1 years. RESULTS: Prevalence of low DXA-derived BMD (Z-score ≤-1) ranged between 21.9% and 25.3%, depending on site (lumbar spine (LS-BMD), femoral neck (FN-BMD), and total body (TB-BMD), and between 3.7% and 5.8% for very low BMD (Z-score ≤-2). Males had a higher prevalence of low BMD than females for all three outcomes (26%-32% vs. 18%-21%), and male sex acted as a significant risk factor for low BMD in all models. Treatment-related factors such as cumulative glucocorticoid (GC) doses and cranial radiation therapy (CRT) were associated with lower BMDs in the full cohort and in females at the FN-BMD site. CONCLUSION: Low and very low BMD is more prevalent in male cALL survivors. Male sex, high cumulative GC doses, CRT, risk group, and low body mass index (BMI) were identified as risk factors for low BMD. A longer follow-up of BMD through time in these survivors is needed to establish if low BMD will translate into a higher risk for fragility fractures through adulthood.

An empirical evaluation of approximate and exact regression-based causal mediation approaches for a binary outcome and a continuous or a binary mediator for case-control study designs.

BACKGROUND: In the causal mediation analysis framework, several parametric regression-based approaches have been introduced in past years for decomposing the total effect of an exposure on a binary outcome into a direct effect and an indirect effect through a target mediator. In this context, a well-known strategy involves specifying a logistic model for the outcome and invoking the rare outcome assumption (ROA) to simplify estimation. Recently, exact estimators for natural direct and indirect effects have been introduced to circumvent the challenges prompted by the ROA. As for the approximate approaches relying on the ROA, these exact approaches cannot be used as is on case-control data where the sampling mechanism depends on the outcome. METHODS: Considering a continuous or a binary mediator, we empirically compare the approximate and exact approaches using simulated data under various case-control scenarios. An illustration of these approaches on case-control data is provided, where the natural mediation effects of long-term use of oral contraceptives on ovarian cancer, with lifetime number of ovulatory cycles as the mediator, are estimated. RESULTS: In the simulations, we found few differences between the performances of the approximate and exact approaches when the outcome was rare, both marginally and conditionally on variables. However, the performance of the approximate approaches degraded as the prevalence of the outcome increased in at least one stratum of variables. Differences in behavior were also observed among the approximate approaches. In the data analysis, all studied approaches were in agreement with respect to the natural direct and indirect effects estimates. CONCLUSIONS: In the case where a violation of the ROA applies or is expected, approximate mediation approaches should be avoided or used with caution, and exact estimators favored.

The association between grip strength and carotid intima media thickness: A Mendelian randomization analysis of the Canadian Longitudinal Study on Aging.

BACKGROUND: Several two-sample Mendelian randomization studies have reported discordant results concerning the association between grip strength and cardiovascular disease, possibly due to the number of instrumental variables used, pleiotropic bias, and/ or effect modification by age and sex. METHODS: We conducted a sex- and age-stratified one-sample Mendelian randomization study in the Canadian Longitudinal Study on Aging. We investigated whether grip strength is associated with carotid intima media thickness (cIMT), a marker of vascular atherosclerosis event risk, using eighteen single nucleotide polymorphisms (SNP) identified as specifically associated with grip strength. RESULTS: A total of 20,258 participants of self-reported European ancestry were included in the analytic sample. Our Mendelian randomization findings suggest a statistically significant association between grip strength and cIMT (MR coefficient of 0.02 (95% CI: 0.01, 0.04)). We found no statistically significant differences between sexes (p-value = 0.201), or age groups [(≤ 60 years old versus >60 years old); p-value = 0.421]. CONCLUSION: This study provides evidence that grip strength is inversely associated with cIMT. Our one-sample MR study design allowed us to demonstrate that there is no evidence of heterogeneity of effects according to age group or biological sex.

Physiological, Anatomical and Metabolic Correlates of Aerobic Fitness in Human Primary Motor Cortex: A Multimodal Study.

Physical activity (PA) has been shown to benefit various cognitive functions and promote neuroplasticity. Whereas the effects of PA on brain anatomy and function have been well documented in older individuals, data are scarce in young adults. Whether high levels of cardiorespiratory fitness (CRF) achieved through regular PA are associated with significant structural and functional changes in this age group remains largely unknown. In the present study, twenty young adults that engaged in at least 8 hours per week of aerobic exercise during the last 5 years were compared to twenty sedentary controls on measures of cortical excitability, white matter microstructure, cortical thickness and metabolite concentration. All measures were taken in the left primary motor cortex and CRF was assessed with VO2max. Transcranial magnetic stimulation (TMS) revealed higher corticospinal excitability in high- compared to low-fit individuals reflected by greater input/output curve amplitude and slope. No group differences were found for other TMS (short-interval intracortical inhibition and intracortical facilitation), diffusion MRI (fractional anisotropy and apparent fiber density), structural MRI (cortical thickness) and magnetic resonance spectroscopy (NAA, GABA, Glx) measures. Taken together, the present data suggest that brain changes associated with increased CRF are relatively limited, at least in primary motor cortex, in contrast to what has been observed in older adults.

Reader reaction to "Outcome-adaptive lasso: Variable selection for causal inference" by Shortreed and Ertefaie (2017).

Shortreed and Ertefaie introduced a clever propensity score variable selection approach for estimating average causal effects, namely, the outcome adaptive lasso (OAL). OAL aims to select desirable covariates, confounders, and predictors of outcome, to build an unbiased and statistically efficient propensity score estimator. Due to its design, a potential limitation of OAL is how it handles the collinearity problem, which is often encountered in high-dimensional data. As seen in Shortreed and Ertefaie, OAL's performance degraded with increased correlation between covariates. In this note, we propose the generalized OAL (GOAL) that combines the strengths of the adaptively weighted L1 penalty and the elastic net to better handle the selection of correlated covariates. Two different versions of GOAL, which differ in their procedure (algorithm), are proposed. We compared OAL and GOAL in simulation scenarios that mimic those examined by Shortreed and Ertefaie. Although all approaches performed equivalently with independent covariates, we found that both GOAL versions were more performant than OAL in low and high dimensions with correlated covariates.

An exact regression-based approach for the estimation of natural direct and indirect effects with a binary outcome and a continuous mediator.

In the causal mediation framework, a number of parametric regression-based approaches have been introduced in recent years for estimating natural direct and indirect effects for a binary outcome in an exact manner, without invoking simplifying assumptions based on the rareness or commonness of the outcome. However, most of these works have focused on a binary mediator. In this article, we aim at a continuous mediator and introduce an exact approach for the estimation of natural effects on the odds ratio, risk ratio, and risk difference scales. Our approach relies on logistic and linear models for the outcome and mediator, respectively, and uses numerical integration to calculate the nested counterfactual probabilities underlying the definition of natural effects. Formulas for the delta method standard errors for all effects estimators are provided. The performance of our proposed exact estimators was evaluated in simulation studies that featured scenarios with different levels of outcome rareness/commonness, including a marginally but not conditionally rare outcome scenario. Furthermore, we evaluated the merit of Firth's penalization to mitigate the bias in the logistic regression coefficients estimators for the smallest outcome prevalences and sample sizes investigated. Using a SAS macro provided, we implemented our approach to assess the effect of placental abruption on low birth weight mediated by gestational age. We found that our exact natural effects estimators worked properly in both simulated and real data applications.

Parametric-Regression-Based Causal Mediation Analysis of Binary Outcomes and Binary Mediators: Moving Beyond the Rareness or Commonness of the Outcome.

In the causal mediation framework, several parametric-regression-based approaches have been introduced in the last decade for estimating natural direct and indirect effects. For a binary outcome, a number of proposed estimators use a logistic model and rely on specific assumptions or approximations that may be delicate or not easy to verify in practice. To circumvent the challenges prompted by the rare outcome assumption in this context, an exact closed-form natural-effects estimator on the odds ratio scale was recently introduced for a binary mediator. In this work, we further push this exact approach and extend it for the estimation of natural effects on the risk ratio and risk difference scales. Explicit formulas for the delta method standard errors are provided. The performance of our proposed exact estimators is demonstrated in simulation scenarios featuring various levels of outcome rareness/commonness. The total effect decomposition property on the multiplicative scales is also examined. Using a SAS macro (SAS Institute, Inc., Cary, North Carolina) we developed, our approach is illustrated to assess the separate effects of exposure to inhaled corticosteroids and placental abruption on low birth weight mediated by prematurity. Our exact natural-effects estimators are found to work properly in both simulations and the real data example.

The impact of adjusting for pure predictors of exposure, mediator, and outcome on the variance of natural direct and indirect effect estimators.

It is now well established that adjusting for pure predictors of the outcome, in addition to confounders, allows unbiased estimation of the total exposure effect on an outcome with generally reduced standard errors (SEs). However, no analogous results have been derived for mediation analysis. Considering the simplest linear regression setting and the ordinary least square estimator, we obtained theoretical results showing that adjusting for pure predictors of the outcome, in addition to confounders, allows unbiased estimation of the natural indirect effect (NIE) and the natural direct effect (NDE) on the difference scale with reduced SEs. Adjusting for pure predictors of the mediator increases the SE of the NDE's estimator, but may increase or decrease the variance of the NIE's estimator. Adjusting for pure predictors of the exposure increases the variance of estimators of the NIE and NDE. Simulation studies were used to confirm and extend these results to the case where the mediator or the outcome is binary. Additional simulations were conducted to explore scenarios featuring an exposure-mediator interaction as well as the relative risk and odds ratio scales for the case of binary mediator and outcome. Both a regression approach and an inverse probability weighting approach were considered in the simulation study. A real-data illustration employing data from the Canadian Study of Health and Aging is provided. This analysis is concerned with the mediating effect of vitamin D in the effect of physical activity on dementia and its results are overall consistent with the theoretical and empirical findings.

The effect of malaria on stunting: an instrumental variables approach.

BACKGROUND: Previous studies have found mixed evidence for an effect of malaria on stunting, but have suffered from concerns about confounding and/or power. Currently, an effect of malaria on stunting is not included in the Lives Saved Tool (LiST) model. METHODS: We used instrumental variables regression with the sickle cell trait and random assignment to bednets as instruments in the analysis of data on children aged 0-2 y from a bednet trial in western Kenya. RESULTS: We estimated that one additional clinical malaria episode per year increases the odds of a child being stunted by 6% (OR estimate: 1.06, 95% CI 1.01 to 1.11). CONCLUSIONS: Our finding that malaria affects stunting suggests that an effect of malaria on stunting in young children should be considered in the LiST model.

Predictors of Vertebral Deformity in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia: The PETALE Study.

BACKGROUND: The prevalence of vertebral deformities in long-term survivors of childhood acute lymphoblastic leukemia (ALL) is unknown. Our objectives were to identify the prevalence of vertebral deformities and their risk factors among long-term childhood ALL survivors. METHODS/RESULTS: We recruited 245 (49% male) long-term childhood ALL survivors from the Preventing Late Adverse Effects of Leukemia Cohort (French-Canadian ALL survivors treated between the years 1987 and 2010 with the Dana Farber Cancer Institute clinical trials protocols, who did not experience disease relapse and/or receive hematopoietic stem cell transplant). Median age at recruitment was 21.7 years (range, 8.5-41) and median time since diagnosis was 15.1 years (range, 5.4-28.2). All participants underwent spine radiograph and dual-energy X-ray absorptiometry scans. The prevalence of vertebral deformity was 23% with 88% classified as grade 1 according to the Genant method. The majority of vertebral deformities were clinically silent. Regression analysis confirmed male sex (risk ratio [RR] = 1.94; 95% confidence interval [CI], 1.16-3.24; P = 0.011), higher glucocorticoid cumulative dose (RR = 1.05; 95% CI, 1.00-1.10; P = 0.032), and back pain (RR = 2.44; 95% CI, 1.56-3.84; P < 0.001) as predictors of prevalent vertebral deformity. Sex differences in vertebral deformity predictors emerged. CONCLUSIONS: We report a significant prevalence of vertebral deformities in this young cohort. Male sex, cumulative glucocorticoid dose, and back pain were identified as predictors of prevalent vertebral deformity. Back pain emerging as a strong predictor of vertebral deformity underscores the importance of ongoing bone health surveillance in survivors with persistent vertebral deformities treated with these earlier protocols.

Diffusion Tensor Imaging in Contact and Non-Contact University-Level Sport Athletes.

Subconcussive hits to the head and physical fitness both have been associated with alterations in white matter (WM) microstructure in partly overlapping areas of the brain. The aim of the present study was to determine whether WM damage associated with repeated exposure to subconcussive hits to the head in university level contact sports athletes is modulated by high levels of fitness. To this end, 72 students were recruited: 24 athletes practicing a varsity contact sport (A-CS), 24 athletes practicing a varsity non-contact sport (A-NCS), and 24 healthy non-athletes (NA). Participants underwent a magnetic resonance imaging session that included diffusion-weighted imaging. Between-groups, statistical analyses were performed with diffusion tensor imaging measures extracted by tractometry of sections of the corpus callosum and the corticospinal tract. Most significant effects were found in A-NCS who exhibited higher fractional anisotropy (FA) values than A-CS in almost all segments of the corpus callosum and in the corticospinal tract. The A-NCS also showed higher FA compared with NA in the anterior regions of the corpus callosum and the corticospinal tracts. No group difference was found between the A-CS and the NA groups. These data suggest that repeated subconcussive hits to the head lead to anisotropic changes in the WM that may counteract the beneficial effects associated with high levels of fitness.

Biomarkers of cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (cALL) are at higher risk of developing cardiometabolic complications. We aimed at exploring the associations between biomarkers of inflammation, oxidative stress, endothelial function, endotoxemia and cardiometabolic risk factors. We conducted a cross-sectional analysis in 246 cALL survivors (mean age, 22.1 ± 6.3 years; mean time since diagnosis, 15.5 ± 5.2 years) and evaluated the associations using a series of logistic regressions. Using structural equation models, we also tested if the relationship between endotoxemia and cardiometabolic complications was mediated by the latent (unobserved) variable inflammation inferred from the observed biomarkers CRP, TNF-α and IL-6. High leptin-adiponectin ratio was associated with obesity [adjusted OR = 15.7; 95% CI (6.2-39.7)], insulin resistance [20.6 (5.2-82.1)] and the metabolic syndrome [11.2 (2.6-48.7)]. Higher levels of plasminogen activator inhibitor-1 and tumor necrosis factor-α were associated with obesity [3.37 (1.6-7.1) and 2.34 (1.3-4.2), respectively] whereas high C-reactive protein levels were associated with insulin resistance [3.3 (1.6-6.8)], dyslipidemia [2.6 (1.4-4.9)] and MetS [6.5 (2.4-17.9)]. Our analyses provided evidence for a directional relationship between lipopolysaccharide binding protein, related to metabolic endotoxemia, inflammation and cardiometabolic outcomes. Identification of biomarkers and biological mechanisms could open new avenues for prevention strategies to minimize the long-term sequelae, improve follow-up and optimize the quality of life of this high-risk population.

Development and internal validation of a multimorbidity index that predicts healthcare utilisation using the Canadian Longitudinal Study on Aging.

OBJECTIVES: We aimed to develop and internally validate a measure of multimorbidity burden using data from the Canadian Longitudinal Study on Aging (CLSA). DESIGN: Data from 40 264 CLSA participants (52% men) aged 45-85 years (a mean of 63 years) were analysed. We used logistic regression models to predict overnight hospitalisation in the last 12 months in the development dataset (random two-thirds of the total) and used these to construct 10 multimorbidity indices (5 models, each treated with and without an age interaction term). Thirty-five chronic conditions were considered for inclusion in these models, in addition to age and sex. We assessed predictive and convergent validity for these 10 different multimorbidity indices in the validation dataset (remaining one-third of the total). RESULTS: The absolute count of chronic conditions plus an interaction with age, displayed strong calibration properties, outperforming other candidate indices. Discrimination was modest for all of the indices that we internally validated, with C-statistics ranging from 0.66 to 0.68. The indices showed weak correlations (ie, convergent validity) with satisfaction with life, functional disability and mental health (absolute Pearson's correlation coefficients ranging from 0.11 to 0.30) but generally moderate correlations with self-rated general health (0.32-0.45). CONCLUSIONS: We investigated alternative methods to measure the multimorbidity burden of individuals, tailored to the CLSA. Our findings show that an absolute count of conditions, along with an age interaction term, has the strongest calibration for overnight hospitalisation in the last 12 months. The utility of an age interaction term in measuring multimorbidity burden may be applicable to the study of chronic disease in cohorts other than the CLSA.

Comparing two counterfactual-outcome approaches in causal mediation analysis of a multicategorical exposure: An application for the estimation of the effect of maternal intake of inhaled corticosteroids doses on birthweight.

Although medical research frequently involves an exposure variable with three or more discrete levels, detailed presentations of mediation techniques for dealing with multicategorical (multilevel) exposures are sparse. In this paper, we study two causal mediation approaches applicable to such a type of exposure for continuous mediator and outcome: the closed-form regression-based approach of Valeri and VanderWeele, and the marginal structural model-based approach of Lange, Vansteelandt, and Bekaert. While the consideration of multicategorical exposures is found explicitly addressed in the literature for the latter approach, this is, to our knowledge, not yet the case for the former. We first illustrate the application of the two aforementioned approaches to assess the dose-response relationship between maternal intake of inhaled corticosteroids and birthweight, where this relationship is potentially mediated by gestational age. More specifically, we provide a precise roadmap for the application of the regression-based approach and of the marginal structural model-based approach on our cohort of pregnancies. Expressions for the natural direct and indirect effects associated with our categorical exposure are provided and, for the regression-based approach, analytic formulas for standard error calculation using the delta method are presented for these effects. Second, a simulation study which mimics our data is presented to add to current knowledge on these causal mediation techniques. Results from this study highlight the relevance to assess robustness of mediation results obtained from multicategorical exposures, most notably for the least prevalent of exposure categories.

Physical Activity and Sedentary Behaviors in Childhood Acute Lymphoblastic Leukemia Survivors.

INTRODUCTION: More than two thirds of survivors have long-term adverse effects, and no study proposes a portrait of physical activity level in childhood acute lymphoblastic leukemia survivors. The aims of this study were to present the cardiorespiratory fitness (CRF) levels of survivors detailed overview sedentary activities portrait. METHODS: A total of 247 childhood acute lymphoblastic leukemia survivors were included in our study. Survivors underwent a cardiopulmonary exercise test on ergocycle and completed physical activity and sedentary questionnaires to assess their leisure physical and sedentary activities and total daily energy expenditure. RESULTS: Up to 67% of survivors (84% below 18 y and 60% 18 y of age or above) did not fulfill the physical activity guidelines. Their CRF was reduced by almost 16% in regard to their predicted maximum oxygen consumption (VO2peak). Almost three quarters of the survivors (70% below 18 y and 76% 18 y of age or above) spent >2 hours/day in leisure sedentary activities. Adult survivors who received high doses of anthracyclines and those who received radiation therapy had decreased odds to spend ≥2 hours/day in sedentary activities. CONCLUSIONS: Our results showed that survivors, especially children, were not active enough and had a reduced CRF. This study highlights the importance of promoting physical activity in survivors, especially because they are exposed to an increased risk of chronic health problems, which could be mitigated by physical activity.

A flexible copula-based approach for the analysis of secondary phenotypes in ascertained samples.

Data collected for a genome-wide association study of a primary phenotype are often used for additional genome-wide association analyses of secondary phenotypes. However, when the primary and secondary traits are dependent, naïve analyses of secondary phenotypes may induce spurious associations in non-randomly ascertained samples. Previously, retrospective likelihood-based methods have been proposed to correct for sampling biases arising in secondary trait association analyses. However, most methods have been introduced to handle studies featuring a case-control design based on a binary primary phenotype. As such, these methods are not directly applicable to more complicated study designs such as multiple-trait studies, where the sampling mechanism also depends on the secondary phenotype, or extreme-trait studies, where individuals with extreme primary phenotype values are selected. To accommodate these more complicated sampling mechanisms, only a few prospective likelihood approaches have been proposed. These approaches assume a normal distribution for the secondary phenotype (or the latent secondary phenotype) and a bivariate normal distribution for the primary-secondary phenotype dependence. In this paper, we propose a unified copula-based approach to appropriately detect genetic variant/secondary phenotype association in the presence of selected samples. Primary phenotype is either binary or continuous and the secondary phenotype is continuous although not necessary normal. We use both prospective and retrospective likelihoods to account for the sampling mechanism and use a copula model to allow for potentially different dependence structures between the primary and secondary phenotypes. We demonstrate the effectiveness of our approach through simulation studies and by analyzing data from the Avon Longitudinal Study of Parents and Children cohort.

Longitudinal assessment of 1H-MRS (GABA and Glx) and TMS measures of cortical inhibition and facilitation in the sensorimotor cortex.

The purpose of the present study was to investigate the long-term stability of water-referenced GABA and Glx neurometabolite concentrations in the sensorimotor cortex using MRS and to assess the long-term stability of GABA- and glutamate-related intracortical excitability using transcranial magnetic stimulation (TMS). Healthy individuals underwent two sessions of MRS and TMS at a 3-month interval. A MEGA-PRESS sequence was used at 3 T to acquire MRS signals in the sensorimotor cortex. Metabolites were quantified by basis spectra fitting and metabolite concentrations were derived using unsuppressed water reference scans accounting for relaxation and partial volume effects. TMS was performed using published standards. After performing stability and reliability analyses for MRS and TMS, reliable change indexes were computed for all measures with a statistically significant test-retest correlation. No significant effect of time was found for GABA, Glx and TMS measures. There was an excellent ICC and a strong correlation across time for GABA and Glx. Analysis of TMS measure stability revealed an excellent ICC for rMT CSP and %MSO and a fair ICC for 2 ms SICI. There was no significant correlation between MRS and TMS measures at any time point. This study shows that MRS-GABA and MRS-Glx of the sensorimotor cortex have good stability over a 3-month period, with variability across time comparable to that reported in other brain areas. While resting motor threshold, %MSO and CSP were found to be stable and reliable, other TMS measures had greater variability and lesser reliability.

Childhood Acute Lymphoblastic Leukemia Survivors Have a Substantially Lower Cardiorespiratory Fitness Level Than Healthy Canadians Despite a Clinically Equivalent Level of Physical Activity.

Introduction: As the survival rate of childhood acute lymphoblastic leukemia (ALL) continues to improve, the physical deconditioning is becoming an increasingly common problem in survivors. The aim of this study was to compare the cardiorespiratory fitness and physical activity levels of survivors and control participants. Methods: A total of 221 childhood ALL survivors (114 males and 107 females), diagnosed between 1987 and 2010 and treated according to Dana Farber Cancer Institute-ALL 87-01 to 05-01 protocols at Sainte-Justine University Health Center (SJUHC), Montreal (Canada), and 825 control participants (364 males and 461 females), recruited in the Canadian Health Measures Survey (cycle 2) during 2009 to 2011 by Statistics Canada, were included in our analyses. In both survivors and controls, cardiorespiratory fitness and moderate to vigorous physical activity (MVPA) were assessed. Results: Survivors' V̇O2 peak was found to be 22% lower than that of controls. Cardiorespiratory fitness was different between the survivors (32.4 ± 8.3 mL/(kg·min); ß = 0.11; 95% confidence interval [CI] 0.07-0.14) and the controls (41.6 ± 9.4 mL/(kg·min); ß = 0.16; 95% CI 0.13-0.18), despite a clinically equivalent level of MVPA [survivors (27.5 ± 27.4 min/day) and controls (33.4 ± 24.2 min/day)]. Status (being survivor) and the age of the participants were negatively associated with cardiorespiratory fitness, whereas MVPA and male gender were positively associated with cardiorespiratory fitness. Conclusion: We observed that for a clinically equivalent level of MVPA, cardiorespiratory fitness was significantly lower in survivors compared with controls. Our findings showed that female survivors were most affected, compared with male survivors. These findings allow further understanding of the physiological differences between childhood ALL survivors and control participants and have important implications for this high-risk population of survivors.

A Bayesian multivariate latent t-regression model for assessing the association between corticosteroid and cranial radiation exposures and cardiometabolic complications in survivors of childhood acute lymphoblastic leukemia: a PETALE study.

BACKGROUND: Childhood acute lymphoblastic leukemia (cALL) is the most frequent pediatric cancer. Over the past decades, treatment of cALL has significantly improved, with cure rates close to 90%. However intensive chemotherapy and cranial radiotherapy (CRT) during a critical period of a child's development have been shown to lead to significant long-term side effects including cardiometabolic complications. Using the PETALE (Prévenir les effets tardifs des traitements de la leucémie aiguë lymphoblastique chez l'enfant) cALL survivor cohort, we investigated the association between combined cumulative corticosteroids (CS) doses and CRT exposures and obesity, insulin resistance, (pre-)hypertension, and dyslipidemia jointly. METHODS: A Bayesian multivariate latent-t model which accounted for our correlated binary outcomes was used for the analyses (n = 241 survivors). CS doses were categorized as low (LD) or high (HD). Combined exposure levels investigated were: 1) LD/no CRT; 2) LD/CRT, and; 3) HD/CRT. We also performed complementary sensitivity analyses for covariate adjustment. RESULTS: Prevalence of cardiometabolic complications ranged from 12.0% for (pre-)hypertension to 40.2% for dyslipidemia. The fully adjusted odds ratio (OR) for dyslipidemia associated with LD/CRT (vs. LD/No CRT) was OR = 1.98 (95% credible interval (CrI): 1.02 to 3.88). LD/CRT level also led to a 0.15 (95% CrI: 0.00 to 0.29) excess risk to develop at least one cardiometabolic complication. Except for obesity, adjusted results for the highest exposure category HD/CRT were generally similar to those for LD/CRT albeit not statistically significant. White blood cell count at diagnosis, a proxy for cALL burden at diagnosis, was found associated with insulin resistance (OR = 1.08 for a 10-unit increase (× 109/L), 95% CrI: 1.02 to 1.14). CONCLUSIONS: Our results indicated that combined LD/CRT exposure is a likely determinant of dyslipidemia among cALL survivors. No evidence was found to suggest that high doses of CS lead to additional risk for obesity, insulin resistance, (pre-)hypertension, and dyslipidemia beyond that induced by CRT. The multivariate model selected for analyses was judged globally useful to assess potential exposure-related concomitance of binary outcomes.

Prevention of Long-term Adverse Health Outcomes With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Most childhood acute lymphoblastic leukemia (ALL) survivors develop chronic treatment-related adverse effects several years after the end of therapy. A regular practice of physical activity and a good cardiorespiratory fitness have the potential to reduce the risk of chronic disease and improve quality of life. The aim of this study was to evaluate in a cohort of ALL survivors, the association between a good cardiorespiratory fitness or the respect of physical activity guidelines and major long-term health outcomes. METHODS: In total, 247 ALL survivors underwent a cardiopulmonary exercise test, completed a physical activity questionnaire and a battery of clinical examinations. We calculated the odds ratio to obtain the preventive fraction (PF) to evaluate the effects of the cardiorespiratory fitness and physical activity levels on health outcomes (ie, obesity, metabolic health, cardiac health, cognitive health and mood, bone health). RESULTS: Despite their young age, 88% of the participants presented at least one adverse health outcome, and 46% presented ≥3. Their cardiorespiratory fitness was also lower than expected with a median VO2 peak reaching 84% of the predicted value. In the analyses using cardiorespiratory fitness, statistically significant PFs were observed for obesity (0.30), low-high-density lipoprotein-cholesterol (0.21) and depression (0.26). In the physical activity level analyses, statistically significant PFs were observed for obesity, depression, and low bone mineral density, with a PF of 0.55, 0.81, and 0.60, respectively. CONCLUSIONS: Our results indicate that a good cardiorespiratory fitness and physical activity level induced a preventive action for most health outcomes studied and was associated with a lower late adverse effects prevalence in ALL survivors.