Person: Betensky, Rebecca
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Betensky
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Rebecca
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Betensky, Rebecca
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Publication Correlation among baseline variables yields non-uniformity of p-values(Public Library of Science, 2017) Betensky, Rebecca; Chiou, Sy HanA recent paper in Neurology used statistical techniques to investigate the integrity of the randomization in 33 clinical trials conducted by a group of investigators. Without justification, the approach assumed that there would be no impact of correlation among baseline variables. We investigated the impact of correlation on the conclusions of the approach in several large-scale simulation studies that replicated the sample sizes and baseline variables of the clinical trials in question and utilized proper randomization. Additionally, we considered scenarios with larger numbers of baseline variables. We found that, with even moderate correlation, there can be substantial inflation of the type I error of statistical tests of randomization integrity. This is also the case under no correlation, in the presence of some discrete baseline variables, with a large number of variables. Thus, statistical techniques for assessing randomization integrity should be applied with extreme caution given that very low p-values, which are taken as evidence against valid randomization, can arise even in the case of valid randomization, in the presence of correlation. More generally, the use of tests of goodness of fit to uniformity for the purpose of testing a global null hypothesis is not advisable in the presence of correlation.Publication Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease(National Academy of Sciences, 2018) Bennett, Rachel; Robbins, Ashley B.; Hu, Miwei; Cao, Xinrui; Betensky, Rebecca; Clark, Tim; Das, Sudeshna; Hyman, BradleyMixed pathology, with both Alzheimer’s disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer’s disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain’s microvasculature.Publication Tau Causes Synapse Loss without Disrupting Calcium Homeostasis in the rTg4510 Model of Tauopathy(Public Library of Science, 2013) Kopeikina, Katherine J.; Wegmann, Susanne; Pitstick, Rose; Carlson, George A.; Bacskai, Brian; Betensky, Rebecca; Hyman, Bradley; Spires-Jones, Tara L.Neurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer’s disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.Publication Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke(Public Library of Science, 2013) Kemmling, André; Lev, Michael; Payabvash, Seyedmehdi; Betensky, Rebecca; Qian, Jing; Masrur, Shihab; Schwamm, LeePurpose Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP. Methods: 215 consecutive acute stroke patients with HAP (2003–2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions. Results: The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP. Conclusions: HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression.Publication Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV(BioMed Central, 2014) Grishchuk, Yulia; Sri, Sarmi; Rudinskiy, Nikita; Ma, Weiyuan; Stember, Katherine G; Cottle, Matthew W; Sapp, Ellen; DiFiglia, Marian; Muzikansky, Alona; Betensky, Rebecca; Wong, Andrew M S; Bacskai, Brian; Hyman, Bradley; Kelleher, Raymond; Cooper, Jonathan D; Slaugenhaupt, SusanMucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1−/− cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0133-7) contains supplementary material, which is available to authorized users.Publication Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses(BioMed Central, 2014) Rudinskiy, Nikita; Hawkes, Jonathan M; Wegmann, Susanne; Kuchibhotla, Kishore V; Muzikansky, Alona; Betensky, Rebecca; Spires-Jones, Tara L; Hyman, BradleyIntraneuronal neurofibrillary tangles (NFTs) – a characteristic pathological feature of Alzheimer’s and several other neurodegenerative diseases – are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.Publication The effect of hospital care on early survival after penetrating trauma(Springer International Publishing, 2014) Clark, David; Doolittle, Peter C; Winchell, Robert J; Betensky, RebeccaBackground: The effectiveness of emergency medical interventions can be best evaluated using time-to-event statistical methods with time-varying covariates (TVC), but this approach is complicated by uncertainty about the actual times of death. We therefore sought to evaluate the effect of hospital intervention on mortality after penetrating trauma using a method that allowed for interval censoring of the precise times of death. Methods: Data on persons with penetrating trauma due to interpersonal assault were combined from the 2008 to 2010 National Trauma Data Bank (NTDB) and the 2004 to 2010 National Violent Death Reporting System (NVDRS). Cox and Weibull proportional hazards models for survival time (tSURV) were estimated, with TVC assumed to have constant effects for specified time intervals following hospital arrival. The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the precise times of death, using an imputation method to accommodate interval censoring along with TVC. Results: All models showed that mortality was increased by older age, female sex, firearm mechanism, and injuries involving the head/neck or trunk. Uncensored models showed a paradoxical increase in mortality associated with the first hour in a hospital. The interval-censored model showed that mortality was markedly reduced after admission to a hospital, with a hazard ratio (HR) of 0.68 (95% CI 0.63, 0.73) during the first 30 min declining to a HR of 0.01 after 120 min. Admission to a verified level I trauma center (compared to other hospitals in the NTDB) was associated with a further reduction in mortality, with a HR of 0.93 (95% CI 0.82, 0.97). Conclusions: Time-to-event models with TVC and interval censoring can be used to estimate the effect of hospital care on early mortality after penetrating trauma or other acute medical conditions and could potentially be used for interhospital comparisons. Electronic supplementary material The online version of this article (doi:10.1186/s40621-014-0024-1) contains supplementary material, which is available to authorized users.Publication Clinical Pertinence Metric Enables Hypothesis-Independent Genome-Phenome Analysis for Neurologic Diagnosis(SAGE Publications, 2014) Segal, Michael M.; Abdellateef, Mostafa; El-Hattab, Ayman W.; Hilbush, Brian S.; De La Vega, Francisco M.; Tromp, Gerard; Williams, Marc S.; Betensky, Rebecca; Gleeson, JosephWe describe an “integrated genome-phenome analysis” that combines both genomic sequence data and clinical information for genomic diagnosis. It is novel in that it uses robust diagnostic decision support and combines the clinical differential diagnosis and the genomic variants using a “pertinence” metric. This allows the analysis to be hypothesis-independent, not requiring assumptions about mode of inheritance, number of genes involved, or which clinical findings are most relevant. Using 20 genomic trios with neurologic disease, we find that pertinence scores averaging 99.9% identify the causative variant under conditions in which a genomic trio is analyzed and family-aware variant calling is done. The analysis takes seconds, and pertinence scores can be improved by clinicians adding more findings. The core conclusion is that automated genome-phenome analysis can be accurate, rapid, and efficient. We also conclude that an automated process offers a methodology for quality improvement of many components of genomic analysis.Publication Application of futility analysis to refine jitter recordings in myasthenia gravis(Wiley-Blackwell, 2012) Narayanaswami, Pushpa; Pantoja-Galicia, Norberto; Betensky, Rebecca; Rutkove, SewardIntroduction The current practice of single fiber electromyography (SFEMG) requires that 20 fiber pairs with normal jitter be collected to exclude myasthenia gravis (MG). We applied principles of futility analysis from clinical trials in an attempt to reduce that requirement. Methods We utilized conditional power futility analysis to assess the probability of an abnormal 20-pair SFEMG based on ongoing analysis of jitter as each pair is collected. Rules for early test termination in the presence of 0, 1 or 2 abnormal pairs were identified. These rules were then applied to previously collected SFEMG data. Results SFEMG could be stopped at just 12 pairs if all are normal and at 17 pairs if 1 is abnormal. The rules successfully determined when SFEMG could be stopped in 104/106 (98%) studies originally reported to be normal. Discussion If the first 12 SFEMG pairs have normal jitter, the study can be terminated and interpreted as normal.Publication APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts(Public Library of Science, 2017) Qian, Jing; Wolters, Frank J.; Beiser, Alexa; Haan, Mary; Ikram, M. Arfan; Karlawish, Jason; Langbaum, Jessica B.; Neuhaus, John M.; Reiman, Eric M.; Roberts, J. Scott; Seshadri, Sudha; Tariot, Pierre N.; Woods, Beth McCarty; Betensky, Rebecca; Blacker, DeborahBackground: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals. Methods and findings We included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables. Conclusions: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.