Rebecca A Betensky
Rebecca Betensky
Scroll
Chair of the Department of Biostatistics
Professor of Biostatistics
-
Professional overview
-
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.
-
Education
-
AB, Mathematics, Harvard University, Cambridge, MAPhD, Statistics, Stanford University, Stanford, CA
-
Areas of research and study
-
BiologyBiostatisticsNeuroepidemiologyNeurologyNeurostatisticsTranslational science
-
Publications
Publications
Primary leptomeningeal lymphoma : International Primary CNS lymphoma collaborative group report
AbstractTaylor, J. W., Flanagan, E. P., O'Neill, B. P., Siegal, T., Omuro, A., DeAngelis, L., Baehring, J., Nishikawa, R., Pinto, F., Chamberlain, M., Hoang-Xuan, K., Gonzalez-Aguilar, A., Batchelor, T., Blay, J. Y., Korfel, A., Betensky, R., Lopes, M. B., & Schiff, D. (n.d.).Publication year
2013Journal title
NeurologyVolume
81Issue
19Page(s)
1690-1696AbstractObjective: To evaluate clinical presentation, optimal diagnostic evaluation and treatment, and outcome in primary leptomeningeal lymphoma, a rare form of primary CNS lymphoma without parenchymal or systemic involvement. Methods: The International Primary CNS Lymphoma Collaborative Group, a multidisciplinary group of physicians with a particular interest in primary CNS lymphoma, retrospectively identified cases of lymphoma isolated to the leptomeninges as diagnosed by CSF cytology, flow cytometry, or biopsy, without systemic or parenchymal brain/spinal cord lymphoma or immunodeficiency. Results: Forty-eight patients were identified, with median age at diagnosis of 51 years and median Eastern Cooperative Oncology Group performance status of 2. Presenting symptoms were multifocal in 68%. Leptomeningeal enhancement was seen in 74% and CSF profile was abnormal in all cases. CSF cytology detected malignant lymphocytes in 67%. Flow cytometry identified monoclonal population in 80%, as did receptor gene rearrangement studies in 71%. Sixty-two percent had B-cell lymphoma, 19% T-cell, and 19% unclassified. Treatment varied and included fractionated radiotherapy (36%), systemic chemotherapy (78%), and intra-CSF chemotherapy (66%), with 66% receiving ≥2 modalities. Seventy-one percent had a favorable clinical response; ultimately, 44% received salvage treatment. Median overall survival was 24 months, with 11 patients still alive at 50 months follow-up. Conclusion: Primary leptomeningeal lymphoma is a rare form of primary CNS lymphoma. Patients usually present with multifocal symptoms, with evidence of leptomeningeal enhancement and diagnostic CSF analysis. Although treatment is highly variable, patients have a better prognosis than previously reported and a subset may be cured.Reply to Sabanés Bové and Held's "Comment on Cai and Betensky (2003), On the Poisson Approximation for Hazard Regression"
Failed retrieving data.Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy
Failed retrieving data.A novel signal processing approach for the detection of copy number variations in the human genome
Failed retrieving data.Application of futility analysis to refine jitter recordings in myasthenia gravis
Failed retrieving data.Calcineurin activation causes retinal ganglion cell degeneration
Failed retrieving data.Corelease of dopamine and GABA by a retinal dopaminergic neuron
AbstractHirasawa, H., Betensky, R., & Raviola, E. (n.d.).Publication year
2012Journal title
Journal of NeuroscienceVolume
32Issue
38Page(s)
13281-13291AbstractNumerous neurons release two transmitters of low molecular mass, but it is controversial whether they are localized within the same synaptic vesicle, with the single exception of GABA and glycine because they are ferried into the vesicle by the same transporter. Retinal dopaminergic (DAergic) amacrine cells synthesize both dopamine (DA) and GABA. Both transmitters are released over the entire cell surface and act on neighboring and distant neurons by volume transmission, but, in addition, DAergic cells establish GABAergic synapses onto AII amacrine cells, the neurons that transfer rod signals to cone bipolars. By combining recordings of DA and GABA release from isolated, genetically identified perikarya of DAergic cells from the mouse retina, we observed that a proportion of the events of DA and GABA exocytosis were simultaneous, suggesting corelease. Furthermore, a proportion of the secretory organelles in the perikaryon and synaptic endings of DAergic cells contained both vesicular transporters for DA [vesicular monoamine transporter 2 (VMAT2)] and GABA [vesicular GABA transporter (VGAT)]. Because the majority of the DA release events concerned a single transmitter and organelles were present that contained a single transporter, either VMAT2 or VGAT, we conclude that the secretory organelles of DAergic cells contain variable concentrations of the two transmitters, which are in turn determined by a variable mixture of the two transporter molecules in their limiting membrane. This variability can be explained if the relative numbers of transporter molecules is determined stochastically during the budding of the somatic organelles from the trans-Golgi network or the retrieval of the vesicular membrane from the plasmalemma after exocytosis.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., 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
Failed retrieving data.Genetic risk factors in Parkinson's disease : Single gene effects and interactions of genotypes
Göbel, A., Macklin, E. A., Winkler, S., Betensky, R., Klein, C., Lohmann, K., & Simon, D. K. (n.d.).Publication year
2012Journal title
Journal of NeurologyVolume
259Issue
11Page(s)
2503-2505Hazard Regression Models of Early Mortality in Trauma Centers
AbstractClark, D. E., Qian, J., Winchell, R. J., & Betensky, R. (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 ScoreIdentification of tissue contamination by polymorphic deletion probe fluorescence in situ hybridization
AbstractChiang, S., Yip, S., Betensky, R., 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
Failed retrieving data.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., 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., 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., 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
Failed retrieving data.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., 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., 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
Failed retrieving data.Supervised Bayesian latent class models for high-dimensional data
AbstractDesantis, S. M., Andrés Houseman, E., Coull, B. A., Nutt, C. L., & Betensky, R. (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. (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., & 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. (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., & 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.