Rebecca A Betensky
Rebecca Betensky
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Chair of the Department of Biostatistics
Professor of Biostatistics
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Professional overview
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Prior to NYU, Dr. Betensky was Professor of Biostatistics at the Harvard T.H. Chan School of Public Health. She was director of the Harvard Catalyst (Clinical and Translational Science Award) Biostatistics Program; director of the Data and Statistics Core for the Massachusetts Alzheimer’s Disease Research Center; and director of the Biostatistics Neurology Core at Massachusetts General Hospital. Previously, she was the Biostatistics Program Leader for the Dana-Farber/Harvard Cancer Center.
Dr. Betensky’s research focuses on methods for the analysis of censored and truncated outcomes and covariates, which frequently arise from the subsampling of cohort studies. She has a long-time interest in clinical trials, and has written on the evaluation of biomarkers and the use and interpretation of p-values. She has collaborated extensively in studies in neurologic diseases, and serves as statistical editor for Annals of Neurology.
Dr. Betensky was awarded, and directed for 15 years, an NIH T32 training program in neurostatistics and neuroepidemiology for pre- and post-doctoral students in biostatistics and epidemiology and for clinician-scientists. She previously directed Harvard’s Biostatistics programs to promote and support diversity at all levels in the field of quantitative public health. She was also a member of the BMRD Study Section for review of NIH statistical methodology grants; on committees for the Institute of Medicine; and a co-chair of the technical advisory committee for the scientific registry of transplant recipients.
Dr. Betensky an elected Fellow of the American Statistical Association and of the International Statistical Institute, and is a past recipient of the Spiegelman Award from the American Public Health Association. She currently serves as a member of the Board of Scientific Counselors for Clinical Science and Epidemiology at the National Cancer Institute.
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Education
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AB, Mathematics, Harvard University, Cambridge, MAPhD, Statistics, Stanford University, Stanford, CA
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Areas of research and study
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BiologyBiostatisticsNeuroepidemiologyNeurologyNeurostatisticsTranslational science
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Publications
Publications
Digital quantification of precursor frequency in the fallopian tube and its significance
AbstractBijron, J. G., Ning, G., Laury, A. R., Quick, C. M., Betensky, R. A., Monte, N. M., King, E., McKeon, F. D., Xian, W., & Crum, C. P. (n.d.).Publication year
2012Journal title
Modern PathologyVolume
25Issue
12Page(s)
1654-1661AbstractA high frequency of precursor lesions is a risk factor for cancer in many organ systems but must be precisely quantified. Pelvic serous neoplasia is associated with an estimated increase in frequency of secretory cell outgrowths (SCOUTs) with loss of PAX2 protein (PAX2p) expression (PAX2p-null SCOUTs) in the fallopian tube. However, to confirm this, PAX2p-null SCOUTs must be precisely quantified relative to the epithelial surface. We developed a method by which fallopian tube sections were digitized using an iScan brightfield scanner (BioImagene) and uploaded in Adobe Photoshop CS3 Extended. Pixel length was translated into microns and epithelial length measured with the Magic Wand tool. SCOUTs were expressed as a function of total epithelial perimeter. Frequency, required perimeter length, topographic clustering tendency and effects of age were ascertained. SCOUT frequency per 10 cm was 0-4.60 for cases and 0-1.66 for controls, averaging 0.84 and 0.27, respectively, (P0.007). Required perimeter length for SCOUT detection was less in serous cancer cases and topographic distribution followed a random pattern without aberrant clustering. Age was also associated with SCOUT frequency (P0.025) and differences between cancers and controls were still significant after adjusting for age (P0.001). We describe an efficient method for quantifying epithelial perimeter in the fallopian tube and verify its relevance to precursor frequency. This has important implications for assessing precursor frequency both in the fallopian tube and in other organs - such as prostate, pancreas and colon - where epithelial precursors are integral to carcinogenesis.Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival
AbstractJansen, M., Mohapatra, G., Betensky, R. A., Keohane, C., & Louis, D. N. (n.d.).Publication year
2012Journal title
Neuropathology and Applied NeurobiologyVolume
38Issue
2Page(s)
213-219AbstractAims: Atypical (World Health Organization grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Post-operative radiotherapy may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array comparative genomic hybridization to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumours show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample. Methods: Eighty-six completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow-up was obtained. Utilizing a dual-colour interphase fluorescence in situ hybridization assay, 1q gain was assessed using Bacterial Artificial Chromosome probes directed against 1q25.1 and 1q32.1. Results: The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas. Conclusions: These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.Genetic risk factors in Parkinson's disease: Single gene effects and interactions of genotypes
Göbel, A., Macklin, E. A., Winkler, S., Betensky, R. A., Klein, C., Lohmann, K., & Simon, D. K. (n.d.). In Journal of Neurology (1–).Publication year
2012Volume
259Issue
11Page(s)
2503-2505Hazard Regression Models of Early Mortality in Trauma Centers
AbstractClark, D. E., Qian, J., Winchell, R. J., & Betensky, R. A. (n.d.).Publication year
2012Journal title
Journal of the American College of SurgeonsVolume
215Issue
6Page(s)
841-849AbstractBackground: Factors affecting early hospital deaths after trauma can be different from factors affecting later hospital deaths, and the distribution of short and long prehospital times can vary among hospitals. Hazard regression (HR) models might therefore be more useful than logistic regression (LR) models for analysis of trauma mortality, especially when treatment effects at different time points are of interest. Study Design: We obtained data for trauma center patients from the 2008-2009 National Trauma Data Bank. Patients were included if they had complete data for prehospital times, hospital times, survival outcomes, age, vital signs, and severity scores. Patients were excluded if pulseless on admission, transferred in or out, or had an Injury Severity Score <9. Using covariates proposed for the Trauma Quality Improvement Program and an indicator for each hospital, we compared LR models predicting survival at 8 hours after injury with HR models with survival censored at 8 hours. Hazard regression models were then modified to allow time-varying hospital effects. Results: A total of 85,327 patients in 161 hospitals met inclusion criteria. Crude hazards peaked initially and then declined steadily. When hazard ratios were assumed constant in HR models, they were similar to odds ratios in LR models associating increased mortality with increased age, firearm mechanism, increased severity, more deranged physiology, and estimated hospital-specific effects. However, when hospital effects were allowed to vary by time, HR models demonstrated that hospital outliers were not the same at different times after injury. Conclusions: Hazard regression models with time-varying hazard ratios reveal inconsistencies in treatment effects, data quality, and/or timing of early death among trauma centers. Hazard regression models are generally more flexible than LR models, can be adapted for censored data, and potentially offer a better tool for analysis of factors affecting early death after injury.Identification of tissue contamination by polymorphic deletion probe fluorescence in situ hybridization
AbstractChiang, S., Yip, S., Betensky, R. A., Batten, J. M., Misdraji, J., & Iafrate, A. J. (n.d.).Publication year
2012Journal title
American Journal of Surgical PathologyVolume
36Issue
10Page(s)
1464-1471AbstractPotential sources of error in surgical pathology include specimen misidentification, unidentified tissue, and tissue contamination of paraffin blocks and slides. Current molecular approaches to characterize unidentified or misidentified tissue include fluorescence in situ hybridization identification of sex chromosomes (XY FISH) and microsatellite analysis. Polymorphic deletion probe (PDP) FISH, a novel FISH assay based on copy number variants, can distinguish between cells and tissues from 2 individuals in situ, independent of gender. Using a panel of 3 PDPs, we compared the genotypes of potential tissue contaminants (n=19) and unidentified tissues (n=6) with patient tissues to determine the utility of PDP FISH in resolving specimen identity. XY FISH was added to increase the informative potential of the assay, and microsatellite analysis was used as a gold standard to confirm PDP FISH results. PDP FISH distinguished between putative contaminants and patient tissues in 13 of 14 cases and indicated a high likelihood of 2 tissues originating from the same source in 11 of 11 cases. The assay has a sensitivity and specificity of 86% [6/7, exact 95% confidence interval (CI): 42%, 97%] and 100% (9/9, exact 1-sided 97.5% CI: 68%, 100%), respectively, and a positive predictive value and negative predictive value of 100% (6/6, exact 1-sided 97.5% CI: 54%, 100%) and 90% (9/10, exact 95% CI: 55%, 98%), respectively. PDP FISH is an accurate and practical molecular assay for the genetic characterization of potential tissue contaminants and unidentified tissues, especially in the setting of small sample size, and permits concomitant assessment of morphology.Imperfect gold standards for kidney injury biomarker evaluation
AbstractWaikar, S. S., Betensky, R. A., Emerson, S. C., & Bonventre, J. V. (n.d.).Publication year
2012Journal title
Journal of the American Society of NephrologyVolume
23Issue
1Page(s)
13-21AbstractClinicians have used serumcreatinine in diagnostic testing for acute kidney injury for decades, despite its imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of acute kidney injury; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, itmay appear inaccurate when using serum creatinine as the gold standard. Acute kidney injury, as defined by serum creatinine, may not reflect tubular injury, and the absence of changes in serum creatinine does not assure the absence of tubular injury. In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury, but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Assuming that, at a certain cutoff value, serum creatinine is 80% sensitive and 90% specific and disease prevalence is 10%, a new perfect biomarker with a true 100% sensitivity may seem to have only 47% sensitivity compared with serum creatinine as the gold standard. Minimizing misclassification by using more strict criteria to diagnose acute kidney injury will reduce the error when evaluating the performance of a biomarker under investigation. Apparent diagnostic errors using a new biomarkermay be a reflection of errors in the imperfect gold standard itself, rather than poor performance of the biomarker. The results of this study suggest that small changes in serum creatinine alone should not be used to define acute kidney injury in biomarker or interventional studies.Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer's disease
AbstractHudry, E., Wu, H. Y., Arbel-Ornath, M., Hashimoto, T., Matsouaka, R., Fan, Z., Spires-Jones, T. L., Betensky, R. A., Bacskai, B. J., & Hyman, B. T. (n.d.).Publication year
2012Journal title
Journal of NeuroscienceVolume
32Issue
9Page(s)
3176-3192AbstractAmyloid β (Aβ) peptides, the main pathological species associated with Alzheimer's disease (AD), disturb intracellular calcium homeostasis, which in turn activates the calcium-dependent phosphatase calcineurin (CaN). CaN activation induced by Aβ leads to pathological morphological changes in neurons, and overexpression of constitutively active calcineurin is sufficient to generate a similar phenotype, even without Aβ. Here, we tested the hypothesis that calcineurin mediates neurodegenerative effects via activation of the nuclear transcription factor of activated T-cells (NFAT). We found that both spine loss and dendritic branching simplification induced by Aβ exposure were mimicked by constitutively active NFAT, and abolished when NFAT activation was blocked using the genetically encoded inhibitor VIVIT. When VIVIT was specifically addressed to the nucleus, identical beneficial effects were observed, thus enforcing the role of NFAT transcriptional activity in Aβ-related neurotoxicity. In vivo, when VIVIT or its nuclear counterpart were overexpressed in a transgenic model of Alzheimer's disease via a gene therapy approach, the spine loss and neuritic abnormalities observed in the vicinity of amyloid plaques were blocked. Overall, these results suggest that NFAT/calcineurin transcriptional cascades contribute to Aβ synaptotoxicity, and may provide a new specific set of pathways for neuroprotective strategies.Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease
AbstractRudinskiy, N., Hawkes, J. M., Betensky, R. A., Eguchi, M., Yamaguchi, S., Spires-Jones, T. L., & Hyman, B. T. (n.d.).Publication year
2012Journal title
Nature NeuroscienceVolume
15Issue
10Page(s)
1422-1429AbstractExperience-induced expression of immediate-early gene Arc (also known as Arg3.1) is known to be important for consolidation of memory. Using in vivo longitudinal multiphoton imaging, we found orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicted the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer's disease, this association was markedly disrupted in the cortex, specifically near senile plaques. Neurons in the vicinity of plaques were less likely to respond, but, paradoxically, there were stronger responses in those few neurons around plaques that did respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to and physiological consolidation of behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration.PAX2-null secretory cell outgrowths in the oviduct and their relationship to pelvic serous cancer
AbstractQuick, C. M., Ning, G., Bijron, J., Laury, A., Wei, T. S., Chen, E. Y., Vargas, S. O., Betensky, R. A., McKeon, F. D., Xian, W., & Crum, C. P. (n.d.).Publication year
2012Journal title
Modern PathologyVolume
25Issue
3Page(s)
449-455AbstractWith the exception of germ-line mutations in ovarian cancer susceptibility genes, genetic predictors for women destined for ovarian serous cancer cannot be identified in advance of malignancy. We recently showed that benign secretory cell outgrowths (SCOUTs) in the oviduct are increased in frequency with concurrent serous cancer and typically lack PAX2 expression (PAX2-null). The present study examined the relationship of PAX2-null SCOUTs to high-grade serous cancers by comparing oviducts from women with benign gynecologic conditions and high-grade serous cancers. PAX2-null SCOUTs were identified by immunostaining and computed as a function of location, frequency (F) per number of cross-sections examined, and age. Six hundred thirty-nine cross-sections from 35 serous cancers (364) and 35 controls (275) were examined. PAX2-null SCOUTs consisted of discrete linear stretches of altered epithelium ranging from cuboidal/columnar, to pseudostratified, the latter including ciliated differentiation. They were evenly distributed among proximal and fimbrial tubal sections. One hundred fourteen (F=0.31) and 45 (F=0.16) PAX2-null SCOUTs were identified in cases and controls, respectively. Mean individual case-specific frequencies for cases and controls were 0.39 and 0.14, respectively. SCOUT frequency increased significantly with age in both groups (P=0.01). However, when adjusted for age and the number of sections examined, the differences in frequency between cases and controls remained significant at P=0.006. This study supports a relationship between discrete PAX2 gene dysregulation in the oviduct and both increasing age and, more significantly, the presence of co-existing serous cancer. We propose a unique co-variable in benign oviductal epithelium-the PAX2-null SCOUT-that reflects underlying dysregulation in genes linked to serous neoplasia.Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy
AbstractGurol, M. E., Dierksen, G., Betensky, R., Gidicsin, C., Halpin, A., Becker, A., Carmasin, J., Ayres, A., Schwab, K., Viswanathan, A., Salat, D., Rosand, J., Johnson, K. A., & Greenberg, S. M. (n.d.).Publication year
2012Journal title
NeurologyVolume
79Issue
4Page(s)
320-326AbstractWe aimed to determine whether amyloid imaging can help predict the location and number of future hemorrhages in cerebral amyloid angiopathy (CAA). We performed a longitudinal cohort study of 11 patients with CAA without dementia who underwent serial brain MRIs after baseline amyloid imaging with Pittsburgh compound B (PiB). Mean distribution volume ratio (DVR) of PiB was determined at the sites of new micro/macrobleeds identified on follow-up MRI and compared with PiB retention at “simulated” hemorrhages, randomly placed in the same subjects using a probability distribution map of CAA-hemorrhage location. Mean PiB retention at the sites of observed new bleeds was also compared to that in shells concentrically surrounding the bleeds. Finally the association between number of incident bleeds and 3 regional amyloid measures were obtained. Nine of 11 subjects had at least one new microbleed on follow-up MRI (median 4, interquartile range [IQR] 1-9) and 2 had 5 new intracerebral hemorrhages. Mean DVR was greater at the sites of incident bleeds (1.34, 95% confidence interval [CI] 1.23-1.46) than simulated lesions (1.14, 95% CI 1.07-1.22, p < 0.0001) in multivariable models. PiB retention decreased with increasing distance from sites of observed bleeds (p < 0.0001). Mean DVR in a superior frontal/parasagittal region of interest correlated independently with number of future hemorrhages after adjustment for relevant covariates (p = 0.003). Our results provide direct evidence that new CAA-related hemorrhages occur preferentially at sites of increased amyloid deposition and suggest that PiB-PET imaging may be a useful tool in prediction of incident hemorrhages in patients with CAA. Aβ: β-amyloid CAA: cerebral amyloid angiopathy CI: confidence interval DVR: distribution volume ratio IQR: interquartile range PiB: Pittsburgh compound B ROI: region of interest SWI: susceptibility-weighted imaging.Reducing available soluble β-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice
AbstractGregory, J. L., Prada, C. M., Fine, S. J., Garcia-Alloza, M., Betensky, R. A., Arbel-Ornath, M., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (n.d.).Publication year
2012Journal title
Journal of Neuropathology and Experimental NeurologyVolume
71Issue
11Page(s)
1009-1017AbstractCerebral amyloid angiopathy (CAA), the accumulation of βamyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment and is commonly associated with Alzheimer disease. The progression of CAA, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain are poorly understood. We manipulated AA levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding "peripheral sink" protein gelsolin and direct inhibition of its formation via administration of LY-411575, a smallmolecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58% ± 0.15% and 0.52% ± 0.09% to 0.11% T 0.18% (p = 0.04) and j0.17% ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. The progression of CAA was also halted when gelsolin was combined with LY-411575 (j0.004% ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ but without evidence of substantial amyloid clearance from vessels.Somatic mitochondrial DNA mutations in early Parkinson and incidental lewy body disease
AbstractLin, M. T., Cantuti-Castelvetri, I., Zheng, K., Jackson, K. E., Tan, Y. B., Arzberger, T., Lees, A. J., Betensky, R. A., Beal, M. F., & Simon, D. K. (n.d.).Publication year
2012Journal title
Annals of NeurologyVolume
71Issue
6Page(s)
850-854AbstractSomatic mutations in mitochondrial DNA (mtDNA) are hypothesized to play a role in Parkinson disease (PD), but large increases in mtDNA mutations have not previously been found in PD, potentially because neurons with high mutation levels degenerate and thus are absent in late stage tissue. To address this issue, we studied early stage PD cases and cases of incidental Lewy body disease (ILBD), which is thought to represent presymptomatic PD. We show for the first time that mtDNA mutation levels in substantia nigra neurons are significantly elevated in this group of early PD and ILBD cases.Stable size distribution of amyloid plaques over the course of alzheimer disease
AbstractSerrano-Pozo, A., Mielke, M. L., Muzitansky, A., Gómez-Isla, T., Growdon, J. H., Bacskai, B. J., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2012Journal title
Journal of Neuropathology and Experimental NeurologyVolume
71Issue
8Page(s)
694-701AbstractAmyloid β plaques are a key pathologic feature of Alzheimer disease (AD), but whether plaque sizes increase or stabilize over the course of AD is unknown. We measured the size distribution of total immunoreactive (10D5-positive) and dense-core (Thioflavin S-positive) plaques in the temporal neocortex of a large group of subjects with AD and age-matched plaque-bearing subjects without dementia to test the hypothesis that amyloid plaques continue to grow along with the progression of the disease. The size of amyloid β (10D5)-positive plaques did not differ between groups, whereas dense-core plaques from the group with AD were slightly larger than those from the group without dementia (∼25%-30%, p = 0.01). Within the group with AD, dense-core plaque size did not independently correlate with duration of clinical disease (from 4 to 21 years, p = 0.68), whereas 10D5-positive plaque size correlated negatively with disease duration (p = 0.01). By contrast, an earlier age of symptom onset strongly predicted a larger postmortem plaque size; this effect was independent of disease duration and the presence of the APOE[Latin Small Letter Open E]4 allele (p = 0.0001). We conclude that plaques vary in size among patients, with larger size distributions correlating with an earlier age of onset, but plaques do not substantially increase in size over the clinical course of the disease.Supervised Bayesian latent class models for high-dimensional data
AbstractDesantis, S. M., Andrés Houseman, E., Coull, B. A., Nutt, C. L., & Betensky, R. A. (n.d.).Publication year
2012Journal title
Statistics in MedicineVolume
31Issue
13Page(s)
1342-1360AbstractHigh-grade gliomas are the most common primary brain tumors in adults and are typically diagnosed using histopathology. However, these diagnostic categories are highly heterogeneous and do not always correlate well with survival. In an attempt to refine these diagnoses, we make several immunohistochemical measurements of YKL-40, a gene previously shown to be differentially expressed between diagnostic groups. We propose two latent class models for classification and variable selection in the presence of high-dimensional binary data, fit by using Bayesian Markov chain Monte Carlo techniques. Penalization and model selection are incorporated in this setting via prior distributions on the unknown parameters. The methods provide valid parameter estimates under conditions in which standard supervised latent class models do not, and outperform two-stage approaches to variable selection and parameter estimation in a variety of settings. We study the properties of these methods in simulations, and apply these methodologies to the glioma study for which identifiable three-class parameter estimates cannot be obtained without penalization. With penalization, the resulting latent classes correlate well with clinical tumor grade and offer additional information on survival prognosis that is not captured by clinical diagnosis alone. The inclusion of YKL-40 features also increases the precision of survival estimates. Fitting models with and without YKL-40 highlights a subgroup of patients who have glioblastoma (GBM) diagnosis but appear to have better prognosis than the typical GBM patient.The distribution of survival times after injury
AbstractClark, D. E., Qian, J., Sihler, K. C., Hallagan, L. D., & Betensky, R. A. (n.d.).Publication year
2012Journal title
World Journal of SurgeryVolume
36Issue
7Page(s)
1562-1570AbstractIntroduction The distribution of survival times after injury has been described as "trimodal," but several studies have not confirmed this. The purpose of this study was to clarify the distribution of survival times after injury. Methods We defined survival time (t s) as the interval between injury time and declared death time. We constructed histograms for t s ≤ 150 min from the 2004-2007 Fatality Analysis Reporting System (FARS, for traffic crashes) and National Violent Death Reporting System (NVDRS, for homicides). We estimated statistical models in which death times known only within intervals were treated as interval-censored. For confirmation, we also obtained EMS response times (t r), prehospital times (t p), and hospital times (t h) for decedents in the 2008 National Trauma Data Bank (NTDB) with t s = t p + t h ≤ 150. We approximated times until circulatory arrest (t x) as t r for patients pulseless at the injury scene, t p for other patients pulseless at hospital admission, and t s for the rest; for any declared t s, we calculated mean t x/t s. We used this ratio to estimate t x for hospital deaths in FARS or NVDRS and provide independent support for using interval-censored methods. Results FARS andNVDRS deathsweremost frequent in the first few minutes. Both showed a second peak at 35-40 min after injury, corresponding to peaks in hospital deaths. Third peakswere not present. Estimated t x in FARS and NVDRS did not show second peaks and were similar to estimates treating some death times as interval-censored. Conclusions Increases in frequency of survival times at 35-40 min are primarily artifacts created because declaration of death in hospitals is delayed until completing resuscitative attempts. By avoiding these artifacts, interval censoring methods are useful for analysis of injury survival times.The SIST-M: Predictive validity of a brief structured clinical dementia rating interview
AbstractOkereke, O. I., Pantoja-Galicia, N., Copeland, M., Hyman, B. T., Wanggaard, T., Albert, M. S., Betensky, R. A., & Blacker, D. (n.d.).Publication year
2012Journal title
Alzheimer disease and associated disordersVolume
26Issue
3Page(s)
225-231AbstractBackground: We have previously established the reliability and cross-sectional validity of the SIST-M (Structured Interview and Scoring Tool-Massachusetts Alzheimer's Disease Research Center), a shortened version of an instrument shown to predict progression to Alzheimer disease (AD), even among persons with very mild cognitive impairment (vMCI). Objective: To test the predictive validity of the SIST-M. Methods: Participants were 342 community-dwelling, nondemented older adults in a longitudinal study. Baseline Clinical Dementia Rating (CDR) ratings were determined by either (1) clinician interviews or (2) a previously developed computer algorithm based on 60 questions (of a possible 131) extracted from clinician interviews. We developed age+sex+education-adjusted Cox proportional hazards models using CDR-sum-of-boxes (CDR-SB) as the predictor, where CDR-SB was determined by either a clinician interview or an algorithm; models were run for the full sample (n=342) and among those jointly classified as vMCI using clinician-based and algorithm-based CDR ratings (n=156). We directly compared predictive accuracy using time-dependent receiver operating characteristic (ROC) curves. Results: AD hazard ratios (HRs) were similar for clinician-based and algorithm-based CDR-SB: for a 1-point increment in CDR-SB, the respective HRs [95% confidence interval (CI)] were 3.1 (2.5, 3.9) and 2.8 (2.2, 3.5); among those with vMCI, the respective HRs (95% CI) were 2.2 (1.6, 3.2) and 2.1 (1.5, 3.0). Similarly high predictive accuracy was achieved: the concordance probability (weighted average of the area-under-the-ROC curves) over follow-up was 0.78 versus 0.76 using clinician-based versus algorithm-based CDR-SB. Conclusion: CDR scores based on items from this shortened interview had high predictive ability for AD-comparable to that using a lengthy clinical interview.A novel signal processing approach for the detection of copy number variations in the human genome
AbstractStamoulis, C., & Betensky, R. A. (n.d.).Publication year
2011Journal title
BioinformaticsVolume
27Issue
17Page(s)
2338-2345AbstractMotivation: Human genomic variability occurs at different scales, from single nucleotide polymorphisms (SNPs) to large DNA segments. Copy number variations (CNVs) represent a signicant part of our genetic heterogeneity and have also been associated with many diseases and disorders. Short, localized CNVs, which may play an important role in human disease, may be undetectable in noisy genomic data. Therefore, robust methodologies are needed for their detection. Furthermore, for meaningful identication of pathological CNVs, estimation of normal allelic aberrations is necessary. Results: We developed a signal processing-based methodology for sequence denoising followed by pattern matching, to increase SNR in genomic data and improve CNV detection. We applied this signal-decomposition-matched ltering (SDMF) methodology to 429 normal genomic sequences, and compared detected CNVs to those in the Database of Genomic Variants. SDMF successfully detected a signicant number of previously identied CNVs with frequencies of occurrence ≥10%, as well as unreported short CNVs. Its performance was also compared to circular binary segmentation (CBS). through simulations. SDMF had a signicantly lower false detection rate and was signicantly faster than CBS, an important advantage for handling large datasets generated with high-resolution arrays. By focusing on improving SNR (instead of the robustness of the detection algorithm), SDMF is a very promising methodology for identifying CNVs at all genomic spatial scales.Association of PGC-1alpha polymorphisms with age of onset and risk of Parkinson's disease
AbstractClark, J., Reddy, S., Zheng, K., Betensky, R. A., & Simon, D. K. (n.d.).Publication year
2011Journal title
BMC Medical GeneticsVolume
12AbstractBackground: Peroxisome proliferator-activated receptor-γ co-activator (PGC)-1α is a transcriptional co-activator of antioxidant genes and a master regulator of mitochondrial biogenesis. Parkinson's disease (PD) is associated with oxidative stress and mitochondrial dysfunction and recent work suggests a role for PGC-1α. We hypothesized that the rs8192678 PGC-1α single nucleotide polymorphism (SNP) may influence risk or age of onset of PD. The A10398G mitochondrial SNP has been inversely associated with risk of PD in some studies. In the current study we analyzed whether rs8192678 or other PGC-1α SNPs affect PD risk or age of onset, singularly or in association with the A10398G SNP.Methods: Genomic DNA samples from 378 PD patients and 173 age-matched controls were analyzed by multiplexed probe sequencing, followed by statistical analyses of the association of each SNP, alone or in combination, with risk or age of onset of PD. Adjustments were made for age of onset being less than the age of sampling, and for the observed dependence between these two ages. The PD samples were obtained as two separate cohorts, therefore statistical methods accounted for different sampling methods between the two cohorts, and data were analyzed using Cox regression adjusted for sampling in the risk set definition and in the model.Results: The rs8192678 PGC-1α SNP was not associated with the risk of PD. However, an association of the PGC-1α rs8192678 GG variant with longevity was seen in control subjects (p = 0.019). Exploratory studies indicated that the CC variant of rs6821591 was associated with risk of early onset PD (p = 0.029), with PD age of onset (p = 0.047), and with longevity (p = 0.022). The rs2970848 GG allele was associated with risk of late onset PD (p = 0.027).Conclusions: These data reveal possible associations of the PGC-1α SNPs rs6821591 and rs2970848 with risk or age of onset of PD, and of the PGC-1α rs8192678 GG and the rs6821591 CC variants with longevity. If replicated in other datasets, these findings may have important implications regarding the role of PGC-1α in PD and longevity.Calcineurin inhibition with systemic FK506 treatment increases dendritic branching and dendritic spine density in healthy adult mouse brain
AbstractSpires-Jones, T. L., Kay, K., Matsouka, R., Rozkalne, A., Betensky, R. A., & Hyman, B. T. (n.d.).Publication year
2011Journal title
Neuroscience lettersVolume
487Issue
3Page(s)
260-263AbstractCalcineurin has been implicated as part of a critical signaling pathway for learning and memory, and recent data suggest that calcineurin activation mediates some of the neurotoxicity of the Alzheimer related neurotoxin Aβ. Immunosuppression via calcineurin inhibition with the compound FK506 is an important treatment for organ transplant patients. Here we use Golgi impregnation techniques, along with a new survival analysis-based statistical approach for analysis of dendritic complexity, to show that in healthy adult mice one week of treatment with FK506 affects both the branching patterns and dendritic spine density of cortical neurons. These results indicate that calcineurin inhibition leads to readily detectable changes in brain morphology, further implicating calcineurin related pathways in both the function and structure of the adult brain.Comparison of clinical subgroup aCGH profiles through pseudolikelihood ratio tests
AbstractEngler, D., Shen, Y., Gusella, J., & Betensky, R. A. (n.d.).Publication year
2011Journal title
Statistical Applications in Genetics and Molecular BiologyVolume
10Issue
1AbstractArray-based Comparative Genomic Hybridization (aCGH) is a microarray-based technology that assists in identification of DNA sequence copy number changes across the genome. Examination of differences in instability phenotype, or pattern of copy number alterations, between cancer subtypes can aid in classification of cancers and lead to better understanding of the underlying cytogenic mechanism. Instability phenotypes are composed of a variety of copy number alteration features including height or magnitude of copy number alteration level, frequency of transition between copy number states such as gain and loss, and total number of altered clones or probes. That is, instability phenotype is multivariate in nature. Current methods of instability phenotype assessment, however, are limited to univariate measures and are therefore limited in both sensitivity and interpretability. In this paper, a novel method of instability assessment is presented that is based on the Engler et al. (2006) pseudolikelhood approach for aCGH data analysis. Through use of a pseudolikelihood ratio test (PLRT), more sensitive assessment of instability phenotype differences between cancer subtypes is possible. Evaluation of the PLRT method is conducted through analysis of a meningioma data set and through simulation studies. Results are shown to be more accurate and more easily interpretable than current measures of instability assessment.Diagnosis of hydatidiform moles by polymorphic deletion probe fluorescence in Situ hybridization
AbstractChiang, S., Fazlollahi, L., Nguyen, A., Betensky, R. A., Roberts, D. J., & Iafrate, A. J. (n.d.).Publication year
2011Journal title
Journal of Molecular DiagnosticsVolume
13Issue
4Page(s)
406-415AbstractBecause products of conception often contain maternal and villous tissues, the determination of maternal and villous genotypes based on genetic polymorphisms can help discern maternal and paternal chromosomal contribution and aid in the diagnosis of hydatidiform moles. Polymorphic deletion probe (PDP) fluorescence in situ hybridization (FISH) probes based on copy number variants are highly polymorphic and allow in situ determination of genetic identity. By using three informative PDPs on chromosomes 2p, 4q, and 8p, we compared maternal with villous genotypes and determined the ploidy of villous tissue. PDP FISH was performed on 13 complete moles, 13 partial moles, 13 nonmolar abortions, and an equivocal hydropic abortion. PDP FISH permitted definitive diagnosis of complete moles in five of 13 cases for which maternal and villous genotypes were mutually exclusive. A complete mole was highly suspected when all three PDP loci showed homozygous villous genotypes. The diagnosis of a complete mole by PDP FISH yielded a theoretical test sensitivity of 87.5%, specificity of 91.8%, an observed test sensitivity of 100%, and specificity of 92.3%. Triploidy was observed in all partial moles, in which diandric triploidy was confirmed in six cases. In the equivocal hydropic abortion, PDP FISH combined with p57 immunofluorescence revealed placental androgenetic/biparental mosaicism. PDP FISH can be used in clinical practice and research studies to subclassify hydatidiform moles and evaluate unusual products of conception.Fallopian tube correlates of ovarian serous borderline tumors
AbstractLaury, A. R., Ning, G., Quick, C. M., Bijron, J., Parast, M. M., Betensky, R. A., Vargas, S. O., McKeon, F. D., Xian, W., Nucci, M. R., & Crum, C. P. (n.d.).Publication year
2011Journal title
American Journal of Surgical PathologyVolume
35Issue
12Page(s)
1759-1765AbstractOvarian serous borderline tumors (SBTs) are presumed to originate in the ovarian cortex or peritoneal surface. The pathogenetic role of the fallopian tube (FT) is unclear; however, recently, secretory cell outgrowths (SCOUTs) lacking PAX2 expression were described in benign FTs. This study addressed (1) the differentiation characteristics of SBTs and (2) the frequency of SCOUTs lacking PAX2 expression in the FTs of patients with SBTs and compared (3) SCOUT morphology and (4) PAX2 expression with SBTs. SBTs and FT epithelium shared both ciliated (p73) and secretory (HMFG2) differentiation. PAX2-null SCOUT frequency in FT cross-sections from patients with SBTs was 0.28 (110 of 398) versus 0.112 in benign hysterectomies and nearly 0 in pediatric and postpartum sterilization specimens (P=<0.001). When adjusted for age, the differences narrowed but remained significant (P=0.010). SCOUTs were heterogeneous, some displaying ciliated differentiation and papillary architecture. Two cases of discrete multifocal papillary SCOUTs in the FTs were associated with SBTs. All SBTs had heterogeneous PAX2 staining with areas of PAX2 loss. This study shows for the first time that PAX2-null SCOUTs are more common in the oviducts of women with SBTs and that loss of PAX2 expression occurs in most SBTs. These discoveries link both morphologic and functional gene (PAX2) alterations in the oviduct to SBTs, similar to that reported in high-grade serous carcinoma. Further study is warranted to clarify the relationship of the oviduct to serous neoplasia.Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: Facilitating analysis of archival gliomas
AbstractMohapatra, G., Engler, D. A., Starbuck, K. D., Kim, J. C., Bernay, D. C., Scangas, G. A., Rousseau, A., Batchelor, T. T., Betensky, R. A., & Louis, D. N. (n.d.).Publication year
2011Journal title
Acta NeuropathologicaVolume
121Issue
4Page(s)
529-543AbstractArray comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas. We first compared aCGH using bacterial artificial chromosome (BAC) arrays in 45 paired frozen and FFPE gliomas, and demonstrate a high concordance rate between FFPE and frozen DNA in an individual clone-level analysis of sensitivity and specificity, assuring that under certain array conditions, frozen and FFPE DNA can perform nearly identically. However, because oligonucleotide arrays offer advantages to BAC arrays in genomic coverage and practical availability, we next developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. To demonstrate utility in FFPE tissues, we applied this approach to biphasic anaplastic oligoastrocytomas and demonstrate CNA differences between DNA obtained from the two components. Therefore, BAC and oligonucleotide aCGH can be sensitive and specific tools for detecting CNAs in FFPE DNA, and novel labeling techniques enable the routine use of oligonucleotide arrays for FFPE DNA. In combination, these advances should facilitate genome-wide analysis of rare, small and/or histologically heterogeneous gliomas from FFPE tissues.Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma
AbstractSnuderl, M., Fazlollahi, L., Le, L. P., Nitta, M., Zhelyazkova, B. H., Davidson, C. J., Akhavanfard, S., Cahill, D. P., Aldape, K. D., Betensky, R. A., Louis, D. N., & Iafrate, A. J. (n.d.).Publication year
2011Journal title
Cancer CellVolume
20Issue
6Page(s)
810-817AbstractTumor heterogeneity has been implicated in tumor growth and progression as well as resistance to therapy. We present an example of genetic heterogeneity in human malignant brain tumors in which multiple closely related driver genes are amplified and activated simultaneously in adjacent intermingled cells. We have observed up to three different receptor tyrosine kinases (EGFR, MET, PDGFRA) amplified in single tumors in different cells in a mutually exclusive fashion. Each subpopulation was actively dividing, and the genetic changes resulted in protein production, and coexisting subpopulations shared common early genetic mutations indicating their derivation from a single precursor cell. The stable coexistence of different clones within the same tumor will have important clinical implications for tumor resistance to targeted therapies.Primary CNS lymphoma in children and adolescents: A descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG)
AbstractAbla, O., Weitzman, S., Blay, J. Y., O’Neill, B. P., Abrey, L. E., Neuwelt, E., Doolittle, N. D., Baehring, J., Pradhan, K., Martin, S. E., Guerrera, M., Shah, S., Ghesquieres, H., Silver, M., Betensky, R. A., & Batchelor, T. (n.d.).Publication year
2011Journal title
Clinical Cancer ResearchVolume
17Issue
2Page(s)
346-352AbstractPurpose: To describe the demographic and clinical features and outcomes for children and adolescents with primary CNS lymphoma (PCNSL). Experimental Design: A retrospective series of children and adolescents with PCNSL was assembled from 10 cancer centers in 3 countries. Results: Twenty-nine patients with a median age of 14 years were identified. Sixteen (55%) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or greater. Frontline therapy consisted of chemotherapy only in 20 patients (69%), while 9 (31%) had chemotherapy plus cranial radiotherapy. Most patients received methotrexate (MTX)-based regimens. Overall response rate was 86% (complete remission 69%, partial remission 17%). The 2-year progression-free survival (PFS) and overall survival (OS) rates were 61% and 86%, respectively; the 3-year OS was 82%. Univariate analyses were conducted for age (≤14 vs. >14 years), PS (0 or 1 vs. >1), deep brain lesions, MTX dose, primary treatment with chemotherapy alone, intrathecal chemotherapy, and high-dose therapy. Primary treatment with chemotherapy alone was associated with better overall response rates with an odds ratio (OR) of 0.125 (P = 0.02). There was a marginally significant relationship between higher doses of MTX and response (OR = 1.5, P = 0.06). ECOG-PS of 0 to 1 was the only factor associated with better outcome with hazard ratios of 0.136 (P = 0.017) and 0.073 (P = 0.033) for PFS and OS, respectively. Conclusion: This is the largest series collected of pediatric PCNSL. The outcome of children and adolescents seems to be better than in adults. PS of 0 to 1 is associated with better survival.