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Browsing by Author "Zhou, Wenxian"
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Item Characteristics and Outcomes of Athletes With Slow Recovery From Sports-Related Concussion: A CARE Consortium Study(Wolters Kluwer, 2023) McAllister, Thomas W.; Broglio, Steven P.; Katz, Barry P.; Perkins, Susan M.; LaPradd, Michelle; Zhou, Wenxian; McCrea, Michael A.; Concussion Assessment, Research and Education (CARE) Consortium; Psychiatry, School of MedicineBackground and objectives: Some athletes experience a slow recovery after sport-related concussion (SRC). There is little agreement on what constitutes slow recovery, however, and minimal data on the prevalence, predictors, or prognosis for this group. The objectives of this study were to apply an operationalized definition of slow recovery and characterize predictors and long-term prognosis of these individuals. Methods: This is a prospective multisite observational study of collegiate athletes. Participants underwent multimodal assessments preseason and 5 additional time points after SRC. Time from injury to initiation of return to play progression (asymptomatic timepoint) and from injury to return to play (RTP) were the primary markers of recovery. Results: One thousand seven hundred fifty-one concussed male and female collegiate athletes were studied. Eighty percent of participants reached the asymptomatic and/or RTP time points by days 14 and 24, respectively. Slow recovery was thus defined as exceeding 1 or both of those intervals (n = 399). This group was statistically more likely to be female (41.1% vs 35.6%, p = 0.05), have higher initial postinjury SCAT symptom severity scores (mean [SD]: 36.6 [23.4] vs 25.4 [19.9], p < 0.001), lower postinjury Standardized Assessment of Concussion scores (mean [SD]:25.74 [2.98] vs 26.26 [2.85], p = 0.004), perform worse on the postinjury Balance Error Scoring System (mean [SD]: 17.8 [8.9] vs 15.9 [8.5], p < 0.01), have fewer assessments in the first 14 days after injury (mean [SD]: 48.8 [29.7] vs 67.9 [24.6], p < 0.01), and be injured in practice (70.7% vs 65.1%, p = 0.04). 77.6% of the slow recovery group returned to play within 60 days of injury, and 83.4% (n = 349) returned to play within 90 days of injury. Only 10.6% had not returned to play 6 months postinjury. Discussion: This study suggests an overall favorable prognosis for slowly recovering athletes and provides data for athletes and medical teams to consider in calibrating RTP expectations and making decisions about medical disqualification vs ongoing engagement in their sport.Item Loss of function of NCOR1 and NCOR2 impairs memory through a novel GABAergic hypothalamus-CA3 projection(Springer Nature, 2019-02) Zhou, Wenjun; He, Yanlin; Rehman, Atteeq U.; Kong, Yan; Hong, Sungguan; Ding, Guolian; Yalamanchili, Hari Krishna; Wan, Ying-Wooi; Paul, Basil; Wang, Chuhan; Gong, Yingyun; Zhou, Wenxian; Liu, Hao; Dean, John; Scalais, Emmanuel; O’Driscoll, Mary; Morton, Jenny E.V.; Hou, Xinguo; Wu, Qi; Tong, Qingchun; Liu, Zhandong; Liu, Pengfei; Xu, Yong; Sun, Zheng; Biostatistics, IU School of MedicineNuclear receptor corepressor 1 (NCOR1) and NCOR2 (also known as SMRT) regulate gene expression by activating histone deacetylase 3 through their deacetylase activation domain (DAD). We show that mice with DAD knock-in mutations have memory deficits, reduced anxiety levels, and reduced social interactions. Mice with NCOR1 and NORC2 depletion specifically in GABAergic neurons (NS-V mice) recapitulated the memory deficits and had reduced GABAA receptor subunit α2 (GABRA2) expression in lateral hypothalamus GABAergic (LHGABA) neurons. This was associated with LHGABA neuron hyperexcitability and impaired hippocampal long-term potentiation, through a monosynaptic LHGABA to CA3GABA projection. Optogenetic activation of this projection caused memory deficits, whereas targeted manipulation of LHGABA or CA3GABA neuron activity reversed memory deficits in NS-V mice. We describe de novo variants in NCOR1, NCOR2 or HDAC3 in patients with intellectual disability or neurodevelopmental disorders. These findings identify a hypothalamus-hippocampus projection that may link endocrine signals with synaptic plasticity through NCOR-mediated regulation of GABA signaling.Item Marginal Regression Analysis of Clustered and Incomplete Event History Data(2022-12) Zhou, Wenxian; Bakoyannis, Giorgos; Zhang, Ying; Yiannoutsos, Constantin T.; Zang, Yong; Hasan, Mohammad AlEvent history data, including competing risks and more general multistate process data, are commonly encountered in biomedical studies. In practice, such event history data are often subject to intra-cluster correlation in multicenter studies and are complicated due to informative cluster size, a situation where the outcomes under study are associated with the size of the cluster. In addition, outcomes or covariates are frequently incompletely observed in real-world settings. Ignoring these statistical issues will lead to invalid inferences. In this dissertation, I develop a series of marginal regression methods to address these statistical issues with competing risks and more general multistate process data. The motivation for this research comes from a large multicenter HIV study and a multicenter randomized oncology trial. First, I propose a marginal regression method for clustered competing risks data with missing cause of failure. I consider the semiparametric proportional cause-specific hazards model and propose a maximum partial pseudolikelihood estimator under a plausible missing at random assumption. Second, I consider more general clustered multistate process data and propose a marginal regression framework for the transient state occupation probabilities. The proposed method is based on a weighted functional generalized estimating equation approach. A nonparametric hypothesis test for the covariate effect is also provided. Third, I extend the proposed framework in the second part of the dissertation to account for missing covariates, via a weighted functional pseudo-expected estimating equation approach. I conduct extensive simulation studies to evaluate the finite sample performance of the proposed methods. The proposed methods are applied to the motivating multicenter HIV study and oncology trial datasets.Item Return to play and risk of repeat concussion in collegiate football players: comparative analysis from the NCAA Concussion Study (1999–2001) and CARE Consortium (2014–2017)(BMJ, 2020) McCrea, Michael; Broglio, Steven P.; McAllister, Thomas; Zhou, Wenxian; Zhao, Shi; Katz, Barry P.; Kudela, Maria; Harezlak, Jaroslaw; Nelson, Lindsay D.; Meier, Timothy B.; Marshall, Stephen W.; Guskiewicz, Kevin; Psychiatry, School of MedicineObjective We compared data from the National Collegiate Athletic Association (NCAA) Concussion Study (1999–2001) and the NCAA-Department of Defense Concussion Assessment, Research and Education (CARE) Consortium (2014–2017) to examine how clinical management, return to play (RTP) and risk of repeat concussion in collegiate football players have changed over the past 15 years. Methods We analysed data on reported duration of symptoms, symptom-free waiting period (SFWP), RTP and occurrence of within-season repeat concussion in collegiate football players with diagnosed concussion from the NCAA Study (n=184) and CARE (n=701). Results CARE athletes had significantly longer symptom duration (CARE median=5.92 days, IQR=3.02–9.98 days; NCAA median=2.00 days, IQR=1.00–4.00 days), SFWP (CARE median=6.00 days, IQR=3.49–9.00 days; NCAA median=0.98 days, IQR=0.00–4.00 days) and RTP (CARE median=12.23 days, IQR=8.04–18.92 days; NCAA median=3.00 days, IQR=1.00–8.00 days) than NCAA Study athletes (all p<0.0001). In CARE, there was only one case of repeat concussion within 10 days of initial injury (3.7% of within-season repeat concussions), whereas 92% of repeat concussions occurred within 10 days in the NCAA Study (p<0.001). The average interval between first and repeat concussion in CARE was 56.41 days, compared with 5.59 days in the NCAA Study (M difference=50.82 days; 95% CI 38.37 to 63.27; p<0.0001). Conclusion Our findings indicate that concussion in collegiate football is managed more conservatively than 15 years ago. These changes in clinical management appear to have reduced the risk of repetitive concussion during the critical period of cerebral vulnerability after sport-related concussion (SRC). These data support international guidelines recommending additional time for brain recovery before athletes RTP after SRC.Item Semiparametric marginal regression for clustered competing risks data with missing cause of failure(Oxford University Press, 2023) Zhou, Wenxian; Bakoyannis, Giorgos; Zhang, Ying; Yiannoutsos, Constantin T.; Biostatistics and Health Data Science, School of MedicineClustered competing risks data are commonly encountered in multicenter studies. The analysis of such data is often complicated due to informative cluster size (ICS), a situation where the outcomes under study are associated with the size of the cluster. In addition, the cause of failure is frequently incompletely observed in real-world settings. To the best of our knowledge, there is no methodology for population-averaged analysis with clustered competing risks data with an ICS and missing causes of failure. To address this problem, we consider the semiparametric marginal proportional cause-specific hazards model and propose a maximum partial pseudolikelihood estimator under a missing at random assumption. To make the latter assumption more plausible in practice, we allow for auxiliary variables that may be related to the probability of missingness. The proposed method does not impose assumptions regarding the within-cluster dependence and allows for ICS. The asymptotic properties of the proposed estimators for both regression coefficients and infinite-dimensional parameters, such as the marginal cumulative incidence functions, are rigorously established. Simulation studies show that the proposed method performs well and that methods that ignore the within-cluster dependence and the ICS lead to invalid inferences. The proposed method is applied to competing risks data from a large multicenter HIV study in sub-Saharan Africa where a significant portion of causes of failure is missing.