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
Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma
AbstractBatchelor, T. T., Betensky, R., Esposito, J. M., Pham, L. D., Dorfman, M. V., Piscatelli, N., Jhung, S., Rhee, D., & Louis, D. N. (n.d.).Publication year
2004Journal title
Clinical Cancer ResearchVolume
10Issue
1 IPage(s)
228-233AbstractPurpose: Although the genetic alterations in glioblastoma have been well characterized, reports regarding their prognostic effects have been inconsistent. Experimental Design: In this series of 140 consecutive cases of glioblastoma treated at a single center, we analyzed the frequency, age dependency and prognostic effects of TP53 mutation, CDKN2A/p16 deletion, EGFR amplification, as well as loss of chromosome 1p, chromosome 10q, and chromosome 19q. The complete set of genetic alterations was available on 60 of 140 patients. Results: In this cohort of glioblastoma cases, TP53 mutation was significantly associated with patient age. The prognostic effects of TP53 mutation, EGFR amplification, CDKN2A/p16 alterations, and loss of chromosome 1p were dependent on the age of the patient. Conclusions: This is the first observation that the prognostic effects of TP53, 1p, and CDKN2A/p16 alterations are dependent on patient age. These observations concerning the interactions of age and genetic changes in glioblastoma suggest that tumorigenic pathways to glioblastoma vary with the age of the patient and that future molecular marker studies should carefully evaluate the potential age-dependent prognostic effects of these biological variables. The inconsistent or negative prognostic effects of molecular markers reported in prior studies of glioblastoma may be because different effects at different ages may have resulted in a cancellation of an overall effect in the entire cohort.Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas
AbstractFernandez-Teijeiro, A., Betensky, R., Sturla, L. M., Kim, J. Y., Tamayo, P., & Pomeroy, S. L. (n.d.).Publication year
2004Journal title
Journal of Clinical OncologyVolume
22Issue
6Page(s)
994-998AbstractPurpose: Stratification of risk in patients with medulloblastoma remains a challenge. As clinical parameters have been proven insufficient for accurately defining disease risk, molecular markers have become the focus of interest. Outcome predictions on the basis of microarray gene expression profiles have been the most accurate to date. We ask in a multivariate model whether clinical parameters enhance survival predictions of gene expression profiles. Patients and Methods: In a cohort of 55 young patients (whose medulloblastoma samples have been analyzed previously for gene expression profile), associations between clinical and gene expression variables and survival were assessed using Cox proportional hazards models. Available clinical variables included age, stage (ie, the presence of disseminated disease at diagnosis), sex, histologic subtype, treatment, and status. Results: Univariate analysis demonstrated expression profiles to be the only significant clinical prognostic factor (P = .03). In multivariate analysis, gene expression profiles predicted outcome independent of other criteria. Clinical criteria did not significantly contribute additional information for outcome predictions, although an exploratory analysis noted a trend for decreased survival of patients with metastases at diagnosis but favorable gene expression profile. Conclusion: Gene expression profiling predicts medulloblastoma outcome independent of clinical variables. These results need to be validated in a larger prospective study.Imaging correlates of molecular signatures in oligodendrogliomas
AbstractMegyesi, J. F., Kachur, E., Lee, D. H., Zlatescu, M. C., Betensky, R., Forsyth, P. A., Okada, Y., Sasaki, H., Mizoguchi, M., Louis, D. N., & Cairncross, J. G. (n.d.).Publication year
2004Journal title
Clinical Cancer ResearchVolume
10Issue
13Page(s)
4303-4306AbstractMolecular subsets of oligodendroglioma behave in biologically distinct ways. Their locations in the brain, rates of growth, and responses to therapy differ with their genotypes. Retrospectively, we inquired whether allelic loss of chromosomal arms 1p and 19q, an early molecular event and favorable prognostic marker in oligodendrogliomas, were reflected in their appearance on magnetic resonance imaging. Loss of 1p and 19q was associated with an indistinct border on T1 images and mixed intensity signal on T1 and T2. Loss of 1p and 19q was also associated with paramagnetic susceptibility effect and with calcification, a common histopathological finding in oligodendrogliomas. These data encourage prospective evaluation of molecular alterations and magnetic resonance imaging characteristics of glial neoplasms.Power Calculations for Familial Aggregation Studies
AbstractRabbee, N., & Betensky, R. (n.d.).Publication year
2004Journal title
Genetic EpidemiologyVolume
26Issue
4Page(s)
316-327AbstractFamily studies are frequently undertaken as the first step in the search for genetic determinants of disease. Significant familial aggregation of disease is suggestive of a genetic etiology for the disease, and may lead to more focused genetic analyses. Many methods have been proposed in the literature for the analysis of family studies. One model that is appealing for its simplicity of computation and the conditional interpretation of its parameters is the quadratic exponential model (e.g., Zhao and Prentice [1990] Biometrika 77:642-648; Betensky and Whittemore [1996] Appl. Stat. 45:422-429; Hudson et al. [2001a] Am. J. Epidemiol. 153:500-514). However, a limiting factor in its application, as well as that of the other proposed methods, is that power and sample size calculations have not been derived. These calculations are essential for investigators who are designing family studies. Here we derive analytic approximations for power for testing for familial aggregation, for both randomly sampled and nonrandomly sampled families. We also present simulation studies of power for both single- and two-disease cases, both under random and nonrandom sampling.The borderline or weakly positive Hybrid Capture II HPV test : A statistical and comparative (PCR) analysis
AbstractFederschneider, J. M., Yuan, L., Brodsky, J., Breslin, G., Betensky, R., & Crum, C. P. (n.d.).Publication year
2004Journal title
American Journal of Obstetrics and GynecologyVolume
191Issue
3Page(s)
757-761AbstractObjectives Recent studies have hypothesized that laboratory contamination may influence interpretation of Hybrid Capture II (HCII) human papillomavirus (HPV) detection assay values. Study design To test this hypothesis, 572 consecutive HCII samples were statistically evaluated to test the null hypothesis that cross-well contamination was not present. In addition, 874 consecutive paired samples from patients followed by both HCII and polymerase chain reaction (PCR) analysis were compared. Results A Kendall's tau measure of association among adjacent wells yielded a P value of .016, rejecting the null hypothesis of no contamination. Analysis of relative light unit values between 0.8 and 1.5 rejected the null hypothesis at P=.077. Moreover, PCR positivity was significantly higher for samples with HCII values above 1.5 vs 0.8 to 1.5 (P=.001). Conclusion Cross-well contamination of samples occurs during processing, and may influence interpretation of some borderline positives. The proportion of cases at risk is low (Treatment of relapsed central nervous system lymphoma with high-dose methotrexate
AbstractPlotkin, S. R., Betensky, R., Hochberg, F. H., Grossman, S. A., Lesser, G. J., Nabors, L. B., Chon, B., & Batchelor, T. T. (n.d.).Publication year
2004Journal title
Clinical Cancer ResearchVolume
10Issue
17Page(s)
5643-5646AbstractPurpose: Over the past decade, high-dose methotrexate has emerged as the single most effective agent in the initial treatment of primary nervous system lymphoma. However, the majority of patients who respond initially to treatment relapse. The optimal management of these patients has not been determined. We performed a multicenter, retrospective study of high-dose methotrexate in patients with relapsed central nervous system lymphoma. Experimental Design: Patients with relapsed disease were eligible if they achieved a complete response to initial treatment with methotrexate-based chemotherapy or received methotrexate after gross total resection of interstitial radiation. All of the patients were retreated with a regimen containing high-dose methotrexate (≥3 g/m2). Results: Twenty-two patients with a median age of 58 years were included in the study. Overall response rates were 91% to first salvage (20 of 22 patients) and 100% to second salvage (4 of 4 patients). Median survival was 61.9 months after first relapse (95% confidence interval, 42.1-∞) and 91.9 months overall (95% confidence interval, 47.2-∞). Toxicity was primarily hematologic with 10 episodes of grade 3 or 4 toxicity during 566 cycles of chemotherapy. Conclusions: These results indicate that high-dose methotrexate remains effective for relapsed central nervous system lymphoma in patients who initially respond to methotrexate and raise the possibility of deferring more toxic salvage regimens in this select group of patients.Analysis of a molecular genetic neuro-oncology study with partially biased selection.
AbstractBetensky, R., Louis, D. N., & Cairncross, J. G. (n.d.).Publication year
2003Journal title
Biostatistics (Oxford, England)Volume
4Issue
2Page(s)
167-178AbstractOligodendrogliomas are a common variant of malignant brain tumors, and are unique for their relative sensitivity to chemotherapy and better prognosis. For these reasons, the identification of an objective oligodendroglial marker has been a long sought-after goal in the field of neuro-oncology. To this end, 75 patients who received chemotherapy at the London Regional Cancer Centre between 1984 and 1999 were studied (Ino et al., Clinical Cancer Research, 7, 839-845, 2001). Of these 75 patients, 50 were initially treated with chemotherapy (the current practice) and comprise a population-based sample. The remaining 25 patients were initially treated with radiation and were included in the study only because their tumor recurred, at which time they received chemotherapy. Because this group of 25 patients included neither those radiation patients whose tumors never recurred nor those radiation patients whose tumors recurred but were not treated with chemotherapy, issues of selection bias were of concern. For this reason, the initial analysis of these data included only the 50 population-based patients. This was unsatisfying given the rarity of this disease and of genetic information on this disease and led us to question whether we could undertake an analysis that includes all of the patients. Here we examine approaches for utilizing the entire study population, as well as the assumptions required for doing so. We illustrate that there are both costs and benefits to using the 25 selected patients.BCL-6 expression predicts improved survival in patients with primary central nervous system lymphoma
AbstractBraaten, K. M., Betensky, R., De Leval, L., Okada, Y., Hochberg, F. H., Louis, D. N., Harris, N. L., & Batchelor, T. T. (n.d.).Publication year
2003Journal title
Clinical Cancer ResearchVolume
9Issue
3Page(s)
1063-1069AbstractPurpose: The purpose of this study was to investigate the histogenetic origin of primary central nervous system lymphoma (PCNSL) with respect to stage of B-cell differentiation and to identify prognostic markers in a cohort of patients with PCNSL treated with i.v. high-dose methotrexate therapy. Experimental Design: This study included 33 patients with PCNSL treated with high-dose i.v. methotrexate at the Massachusetts General Hospital for whom archival tumor tissue was available. All 33 patients tested negative for HIV. The lymphomas were morphologically subclassified according to the Kiel system, as modified in the WHO classification. Immunohistochemistry for the following antigens was performed: BCL-6; BCL-2; MUM1; CD10; vs38c; CD138; CD44; p16; and p53. Fluorescence in situ hybridization and multiplex PCR for CDKN2A/p16 were also performed. Results: There were 17 women and 16 men enrolled, with a median age of 60 years. All tumors were diffuse large B-cell lymphomas. Of the 23 cases that could be subclassified, 22 were centroblastic, and 1 was immunoblastic. Twenty-six of 33 tumors were BCL-6+, 6 of 32 tumors were CD10+, 27 of 29 tumors were BCL-2+, 31 of 32 tumors were MUM1+, 11 of 31 tumors were CD44+, 4 of 33 tumors were vs38c+, and 0 of 32 tumors were CD138+. There were 18 of 32 (56%) complete responses and 8 of 32 (25%) partial responses to methotrexate, whereas 6 of 33 (18%) progressed during treatment. Ten patients died of disease. Expression of BCL-6 was significantly associated with longer overall survival (P = 0.002; median survival, 101 versus 14.7 months, with approximately 95% lower confidence limits of 41.7 and 8.8 months, respectively). Conclusions: In this group of 33 patients with PCNSL, expression of BCL-6 was significantly associated with longer overall survival. BCL-6 warrants further investigation as a potentially important prognostic marker in this disease.Commentary : Failure-rate functions for doubly-truncated random variables
AbstractBetensky, R., & Martin, E. C. (n.d.).Publication year
2003Journal title
IEEE Transactions on ReliabilityVolume
52Issue
1Page(s)
7-8AbstractNavarro and Ruiz [1] express the nonparametric maximum likelihood estimator (NPMLE) of the distribution of a failure-time random variable as a function of the NPMLE of generalized failure-rate functions. These generalized failure-rate functions are equal to the probability density functions of a doubly-truncated failure-time random variable at the endpoints of the truncating interval. Readers can infer from this paper that this simple estimator can be applied to a doubly-truncated sample of failure times. This commentary explains why that estimator does not apply to the general setting in which the observed failure times are doubly-truncated with subject-specific truncating intervals. A doubly-truncated sample of times to brain tumor progression illustrates the deviation of that estimator [1] from the NPMLE for these data. Definitions Quasar: unusually luminous objects found in remote areas of the universe; stellar object: nonquasar object; redshift: the shift in an object'S spectral lines toward the red end, indicating how fast the object is moving away from the observer.Gene expression-based classification of malignant gliomas correlates better with survival than histological classification
AbstractNutt, C. L., Mani, D. R., Betensky, R., Tamayo, P., Cairncross, J. G., Ladd, C., Pohl, U., Hartmann, C., McLaughlin, M. E., Batchelor, T. T., Black, P. M., Von Deimling, A., Pomeroy, S. L., Golub, T. R., & Louis, D. N. (n.d.).Publication year
2003Journal title
Cancer ResearchVolume
63Issue
7Page(s)
1602-1607AbstractIn modern clinical neuro-oncology, histopathological diagnosis affects therapeutic decisions and prognostic estimation more than any other variable. Among high-grade gliomas, histologically classic glioblastomas and anaplastic oligodendrogliomas follow markedly different clinical courses. Unfortunately, many malignant gliomas are diagnostically challenging; these nonclassic lesions are difficult to classify by histological features, generating considerable interobserver variability and limited diagnostic reproducibility. The resulting tentative pathological diagnoses create significant clinical confusion. We investigated whether gene expression profiling, coupled with class prediction methodology, could be used to classify high-grade gliomas in a manner more objective, explicit, and consistent than standard pathology. Microarray analysis was used to determine the expression of ∼12,000 genes in a set of 50 gliomas, 28 glioblastomas and 22 anaplastic oligodendrogliomas. Supervised learning approaches were used to build a two-class prediction model based on a subset of 14 glioblastomas and 7 anaplastic oligodendrogliomas with classic histology. A 20-feature κ-nearest neighbor model correctly classified 18 of the 21 classic cases in leave-one-out cross-validation when compared with pathological diagnoses. This model was then used to predict the classification of clinically common, histologically nonclassic samples. When tumors were classified according to pathology, the survival of patients with nonclassic glioblastoma and nonclassic anaplastic oligodendroglioma was not significantly different (P = 0.19). However, class distinctions according to the model were significantly associated with survival outcome (P = 0.05). This class prediction model was capable of classifying high-grade, nonclassic glial tumors objectively and reproducibly. Moreover, the model provided a more accurate predictor of prognosis in these nonclassic lesions than did pathological classification. These data suggest that class prediction models, based on defined molecular profiles, classify diagnostically challenging malignant gliomas in a manner that better correlates with clinical outcome than does standard pathology.Hazard regression for interval-censored data with penalized spline
AbstractCai, T., & Betensky, R. (n.d.).Publication year
2003Journal title
BiometricsVolume
59Issue
3Page(s)
570-579AbstractThis article introduces a new approach for estimating the hazard function for possibly interval- and right-censored survival data. We weakly parameterize the log-hazard function with a piecewise-linear spline and provide a smoothed estimate of the hazard function by maximizing the penalized likelihood through a mixed model-based approach. We also provide a method to estimate the amount of smoothing from the data. We illustrate our approach with two well-known interval- censored data sets. Extensive numerical studies are conducted to evaluate the efficacy of the new procedure.Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis
AbstractBai, H., Cviko, A., Granter, S., Yuan, L., Betensky, R., & Crum, C. P. (n.d.).Publication year
2003Journal title
Human PathologyVolume
34Issue
6Page(s)
559-564AbstractHuman papillomavirus (HPV) infections of the genital mucosa classically present as warts (condylomata) and are traditionally defined by the presence of viral cytopathic effect (koilocytosis). In recent years, HPV has been detected in vulvar epithelial changes lacking koilocytosis, including squamous papillomas and lesions closely resembling seborrheic keratosis (SK). The purpose of this study was to determine the frequency and type of HPV associated with vulvar SK (VSK) and to compare expression of biomarkers (p16, Mib-1, and cyclin E) in these lesions. Sixty-seven biopsy specimens, including 25 VSKs, 10 nondiagnostic vulvar acanthoses, 12 fibroepithelial polyps (FEPs), and 20 nongenital cutaneous SKs (CSKs), were studied. Biopsy specimens were typed for HPV by polymerase chain reaction and immunostained with Mib-1, cyclin E, and p16INK4 antibodies. Eighteen of 25 VSKs (72%), 0 of 10 nondiagnostic vulvar acanthuses (0%; P = 0.0001), 2 of 12 FEPs (16.7%; P = 0.004), and 3 of 20 CSKs (15%; P = 0.0002) scored HPV positive. Increased Mib-1 staining was significantly more common in VSKs than in other vulvar lesions, but not in CSKs; increased p16 and cyclin E staining was not more common. VSKs are morphologically and immunophenotypically similar to CSKs but distinct by their association with HPV. Unlike the cervix, p16 and cyclin E will not consistently distinguish VSKs from HPV-negative lesions due to underexpression in low-risk HPV infections (p16) and less-restricted expression in vulvar lesions (cyclin E). Whether CSKs are associated with other forms of HPV infection remains to be determined.Malignant peripheral nerve sheath tumor : The clinical spectrum and outcome of treatment
AbstractBaehring, J. M., Betensky, R., & Batchelor, T. T. (n.d.).Publication year
2003Journal title
NeurologyVolume
61Issue
5Page(s)
696-698AbstractMalignant peripheral nerve sheath tumors (MPNST) are derived from Schwann cells or pluripotent cells of the neural crest. Delay of diagnosis is common, especially in lesions affecting proximal parts of the peripheral nervous system. Presented is a series of 54 patients with MPNST seen at a single institution over a 10-year period. In this series, tumor diameter ofNeurolymphomatosis
AbstractBaehring, J. M., Damek, D., Martin, E. C., Betensky, R., & Hochberg, F. H. (n.d.).Publication year
2003Journal title
Neuro-OncologyVolume
5Issue
2Page(s)
104-115AbstractThe term "neurolymphomatosis" (NL) has included infiltration of the peripheral nervous system by lymphoma and nontumor lymphocytes. We describe NL as a lymphoma entity that affects cranial and peripheral nerves and roots. We reviewed the medical records of patients at the Massachusetts General Hospital (MGH) who registered between 1972 and 2000, as well as cases published in the English-language literature. Inclusion criteria were (A) histopathologic demonstration of lymphoma within peripheral nerve, nerve root/plexus, or cranial nerve or (B) CT/MRI or intraoperative evidence of nerve enlargement and/or enhancement beyond the dural sleeve in the setting of prior or concurrent lymphoma in systemic or CNS sites. We identified 25 patients with NL in addition to 47 reported by others. Four clinical presentations were (1) painful involvement of nerves or roots, (2) cranial neuropathy with or without pain, (3) painless involvement of peripheral nerves, (4) painful or painless involvement of a single peripheral nerve. Twenty of our patients and 44 of those reported had histopathologic confirmation of lymphoma infiltrating root or nerve. In the remainder, diagnosis was based upon clinical presentation, nodular nerve enlargement or enhancement, and lymphoma cells in spinal fluid or extraneural sites. For antemortem diagnosis, imaging studies were of greatest utility, followed by biopsy. Thirty-three patients of the combined series were not correctly diagnosed until postmortem examination. Systemic chemotherapy was used to address the multiple potential sites of involvement. When properly treated, NL carries a prognosis similar to primary CNS lymphoma in the modern era.The Leapfrog Volume Criteria May Fall Short in Identifying High-Quality Surgical Centers
AbstractChristian, C. K., Gustafson, M. L., Betensky, R., Daley, J., Greenfield, L. J., Rhodes, R. S., & Zinner, M. J. (n.d.).Publication year
2003Journal title
Annals of SurgeryVolume
238Issue
4Page(s)
447-457AbstractObjective: The original Leapfrog Initiative recommends selective referral based on procedural volume thresholds (500 coronary artery bypass graft [CABG] surgeries, 30 abdominal aortic aneurysm [AAA] repairs, 100 carotid endarterectomies [CEA], and 7 esophagectomies annually). We tested the volume-mortality relationship for these procedures in the University HealthSystem Consortium (UHC) Clinical DatabaseSM, a database of all payor discharge abstracts from UHC academic medical center members and affiliates. We determined whether the Leapfrog thresholds represent the optimal cutoffs to discriminate between high- and low-mortality hospitals. Methods: Logistic regression was used to test whether volume was a significant predictor of mortality. Volume was analyzed in 3 different ways: as a continuous variable, a dichotomous variable (above and below the Leapfrog threshold), and a categorical variable. We examined all possible thresholds for volume and observed the optimal thresholds at which the odds ratio is the highest, representing the greatest difference in odds of death between the 2 groups of hospitals. Results: In multivariate analysis, a relationship between volume and mortality exists for AAA in all 3 models. For CABG, there is a strong relationship when volume is tested as a dichotomous or categorical variable. For CEA and esophagectomy, we were unable to identify a consistent relationship between volume and outcome. We identified empirical thresholds of 250 CABG, 15 AAA, and 22 esophagectomies, but were unable to find a meaningful threshold for CEA. Conclusions: In this group of academic medical centers and their affiliated hospitals, we demonstrated a significant relationship between volume and mortality for CABG and AAA but not for CEA and esophagectomy, based on the Leapfrog thresholds. We described a new methodology to identify optimal data-based volume thresholds that may serve as a more rational basis for selective referral.A local likelihood proportional hazards model for interval censored data
AbstractBetensky, R., Lindsey, J. C., Ryan, L. M., & Wand, M. P. (n.d.).Publication year
2002Journal title
Statistics in MedicineVolume
21Issue
2Page(s)
263-275AbstractWe discuss the use of local likelihood methods to fit proportional hazards regression models to right and interval censored data. The assumed model allows for an arbitrary, smoothed baseline hazard on which a vector of covariates operates in a proportional manner, and thus produces an interpretable baseline hazard function along with estimates of global covariate effects. For estimation, we extend the modified EM algorithm suggested by Betensky, Lindsey, Ryan and Wand. We illustrate the method with data on times to deterioration of breast cosmeses and HIV-1 infection rates among haemophiliacs.C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke
AbstractBetensky, R., Arboleda-Velasquez, J. F., Lopera, F., Lopez, E., Frosch, M. P., Sepulveda-Falla, D., Gutierrez, J. E., Vargas, S., Medina, M., Martinez De Arrieta, C., Lebo, R. V., Slaugenhaupt, S. A., Betensky, R. A., Villegas, A., Arcos-Burgos, M., Rivera, D., Restrepo, J. C., & Kosik, K. S. (n.d.).Publication year
2002Journal title
NeurologyVolume
59Issue
2Page(s)
277-279AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the notch3 epidermal growth factor-like repeats. A Colombian kindred carries a novel C455R mutation located in the predicted ligand-binding domain. Stroke occurred in the patients at an unusually early age (median age: 31 years) in comparison to the more frequent onset in the fourth decade of life in other CADASIL populations, including a second Colombian kindred with an R1031C mutation.DMBT1 polymorphisms : Relationship to malignant glioma tumorigenesis
AbstractSasaki, H., Betensky, R., Cairncross, J. G., & Louis, D. N. (n.d.).Publication year
2002Journal title
Cancer ResearchVolume
62Issue
6Page(s)
1790-1796AbstractThe deleted in malignant brain tumors 1 (DMBT1) gene on 10q25-26 is a candidate tumor suppressor gene in malignant gliomas, but its role is controversial, e.g., some DMBT1 homozygous deletions reflect unmasking of constitutional deletion polymorphisms by 10q loss. To clarify the role of DMBT1 in gliomagenesis, we investigated three reported deletion hot spots. Homozygous deletions at DMBT1 repeat 2-4 to 2-7 were found in 10 of 73 gliomas with 10q loss, but all 10 deletions reflected unmasking of constitutional hemizygous deletions. Alleles bearing deletion 2-4/2-7 were not selected significantly for by 10q loss, with retention of only 10 of 16 deleted alleles. No homozygous deletion was detected at locus 74k in the 5′ upstream region of DMBT1, and four tightly linked polymorphisms were found around this region; chromosome 10q loss randomly affected alleles with or without the variant sequences around locus 74k. Moreover, no significant selection pressure was detected for the haplotype with both deletion 2-4/2-7 and 5′ polymorphisms. There was no segregation of deletion 2-4/2-7 in glioma patients compared with unrelated individuals from reference families but a suggestion of a difference in the distribution of the 5′ polymorphisms between the reference individuals and glioma patients. Constitutional polymorphisms at DMBT1 repeat 2-9/2-10 appeared common in patients with both benign brain tumors and gliomas. A homozygote for both the 2-4/2-7 deletion and the 5′ polymorphisms had a glioma arise at a typical age and without an apparent family cancer predisposition. These data suggest that DMBT1 polymorphisms are not likely primary targets of 10q loss in malignant gliomas and do not support a major role for DMBT1 in gliomagenesis.Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade "oligodendroglioma"
AbstractBetensky, R., Sasaki, H., Zlatescu, M. C., Betensky, R. A., Johnk, L. B., Cutone, A. N., Cairncross, J. G., & Louis, D. N. (n.d.).Publication year
2002Journal title
Journal of Neuropathology and Experimental NeurologyVolume
61Issue
1Page(s)
58-63AbstractAllelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 "astrocytic" gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.Influence of unrecognized molecular heterogeneity on randomized clinical trials
AbstractBetensky, R., Louis, D. N., & Cairncross, J. G. (n.d.).Publication year
2002Journal title
Journal of Clinical OncologyVolume
20Issue
10Page(s)
2495-2499AbstractPurpose: In solid tumor oncology, decisions regarding treatment and eligibility for trials are governed by histologic diagnosis. Despite this reliance on histology and the assumption that histology defines the disease, underlying molecular heterogeneity likely differentiates among patients' outcomes. Patients and Methods: To illustrate how unrecognized molecular heterogeneity might obscure a truly effective new therapy for cancer, we analyzed the planning assumptions and results of a hypothetical randomized controlled trial of chemoradiotherapy for a cancer found to be drug sensitive in preliminary phase II studies. Results: Randomized controlled trials of effective cancer therapies can be falsely negative if therapeutic benefit is overestimated during study design because of enrichment of phase II trials for treatment-sensitive subtypes, a beneficial effect in responding patients is diluted by large numbers of nonresponding patients, or a beneficial effect in responders is reversed by a negative effect in nonresponders. Conclusion: Molecular heterogeneity, if it confers different risks to patients and is unaccounted for in the design of a randomized study, can result in a clinical trial that is underpowered and fails to detect a truly effective new therapy for cancerLocal likelihood analysis of the latency distribution with interval censored intermediate events
AbstractBebchuk, J. D., & Betensky, R. (n.d.).Publication year
2002Journal title
Statistics in MedicineVolume
21Issue
22Page(s)
3475-3491AbstractThe distribution of time between an intermediate event and a terminal event is frequently of interest both in studying the behaviour of populations and in predicting outcomes for individuals. Current methods for estimating this latency distribution have either imposed assumptions on the hazard for the terminal event following the occurrence of the intermediate event or on the parametric form of the hazards. Here, local likelihood estimation is applied to the underlying hazard functions of a three-state process in which the time of the intermediate event may be interval censored and the time of the terminal event is either observed or right censored. Smooth non-parametric estimates of the latency distribution, along with bootstrap confidence intervals, are calculated, and tests for the comparison of two latency distributions are presented. The method is applied to two studies: a cohort of haemophiliacs who were infected with HIV by contaminated blood factor and followed for AIDS onset, and an AIDS clinical trial in which the intermediate event is the time to 50 per cent drop in CD4 count and the terminal event is AIDS or death. Simulations are presented to assess the performance of the estimation procedure.Sample size re-estimation in cluster randomization trials
AbstractLake, S., Kammann, E., Klar, N., & Betensky, R. (n.d.).Publication year
2002Journal title
Statistics in MedicineVolume
21Issue
10Page(s)
1337-1350AbstractCluster randomization trials in which families are the unit of allocation are commonly adopted for the evaluation of disease prevention interventions. Sample size estimation for cluster randomization trials depends on parameters that quantify the variability within and between clusters and the variability in cluster size. Accurate advance estimates of these nuisance parameters may be difficult to obtain and misspecification may lead to an underpowered study. Since families are typically recruited over time, we propose using a portion of the data to estimate the nuisance parameters and to re-estimate sample size based on the estimates. This extends the standard internal pilot study methods to the setting of cluster randomization trials. The effect of this design on the power, significance level and sample size is analysed via simulation and is shown to provide a flexible and practical approach to cluster randomization trials.Testing for dependence between failure time and visit compliance with interval-censored data
AbstractBetensky, R., Betensky, R. A., & Finkelstein, D. M. (n.d.).Publication year
2002Journal title
BiometricsVolume
58Issue
1Page(s)
58-63AbstractInterval-censored failure-time data arise when subjects miss prescheduled visits at which the failure is to be assessed. The resulting intervals in which the failure is known to have occurred are overlapping. Most approaches to the analysis of these data assume that the visit-compliance process is ignorable with respect to likelihood analysis of the failure-time distribution. While this assumption offers considerable simplification, it is not always plausible. Here we test for dependence between the failure- and visit-compliance processes, applicable to studies in which data collection continues after the occurrence of the failure. We do not make any of the assumptions made by previous authors about the joint distribution of the visit-compliance process, a covariate process, and the failure time. Instead, we consider conditional models of the true failure history given the current visit compliance at each visit time, allowing for correlation across visit times. Because failure status is not known at some visit times due to missed visits, only models of the observed failure history given current visit compliance are estimable. We describe how the parameters from these models can be used to test for a negative association and how bounds on unestimable parameters provided by the observed data are needed additionally to infer a positive association. We illustrate the method with data from an AIDS study and we investigate the power of the test through a simulation study.The use of frailty hazard models for unrecognized heterogeneity that interacts with treatment : Considerations of efficiency and power
AbstractBetensky, R., Li, Y., Betensky, R. A., Louis, D. N., & Cairncross, J. G. (n.d.).Publication year
2002Journal title
BiometricsVolume
58Issue
1Page(s)
232-236AbstractIncreasingly, genetic studies of tumors of the same histologic diagnosis are elucidating subtypes that are distinct with respect to clinical endpoints such as response to treatment and survival. This raises concerns about the efficiency of using the simple log-rank test for analysis of treatment effect on survival in studies of possibly heterogeneous tumors. Furthermore, such studies, designed under the assumption of homogeneity, may be severely underpowered. We derive analytic approximations for the asymptotic relative efficiency of the simple log-rank test relative to the optimally weighted log-rank test and for the power of the simple log-rank test when applied to subjects with unobserved heterogeneity, as reflected in a continuous frailty, that may interact with treatment. Numerical studies demonstrate that the simple log-rank test may be quite inefficient if the frailty interacts with treatment. Further, there may be a substantial loss of power in the presence of the frailty with or without an interaction with treatment.A comparison of models for clustered binary outcomes : Analysis of a designed immunology experiment
AbstractBetensky, R., Williams, P. L., & Lederman, H. M. (n.d.).Publication year
2001Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
50Issue
1Page(s)
43-61AbstractThe lymphocyte proliferative assay (LPA) of immune competence was conducted on 52 subjects, with up to 36 processing conditions per subject, to evaluate whether samples could be shipped or stored overnight, rather than being processed on fresh blood as currently required. The LPA study resulted in clustered binary data, with both cluster level and cluster-varying covariates. Two modelling strategies for the analysis of such clustered binary data are through the cluster-specific and population-averaged approaches. Whereas most research in this area has focused on the analysis of matched pairs data, in many situations, such as the LPA study, cluster sizes are naturally larger. Through considerations of interpretation and efficiency of these models when applied to large clusters, the mixed effect cluster-specific model was selected as most appropriate for the analysis of the LPA data. The model confirmed that the LPA response is significantly impaired in individuals infected with the human immunodeficiency virus (HIV). The LPA response was found to be significantly lower for shipped and overnight samples than for fresh samples, and this effect was significantly stronger among HIV-infected individuals. Surprisingly, an anticoagulant effect was not detected.