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
Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy
AbstractRosand, J., Muzikansky, A., Kumar, A., Wisco, J. J., Smith, E. E., Betensky, R. A., & Greenberg, S. M. (n.d.).Publication year
2005Journal title
Annals of NeurologyVolume
58Issue
3Page(s)
459-462AbstractCerebral amyloid angiopathy (CAA) is a common cause of symptomatic intracerebral hemorrhage (ICH), as well as small asymptomatic hemorrhage in the elderly. We used gradient-echo MRI to analyze spatial distribution of 321 hemorrhages in 59 patients with probable CAA-related ICH. Hemorrhagic lesions were found preferentially in the temporal (ratio of actual to expected hemorrhages = 1.37) and occipital lobes (ratio = 1.45, p < 0.0001). Within individuals, hemorrhages tended to cluster, regardless of lobe (p < 0.0001). Among subjects followed prospectively for recurrence, clustering of new symptomatic and asymptomatic hemorrhages was observed. These data suggest that regional differences within the brain play a role in the development of CAA-related hemorrhage.Statistical considerations for immunohistochemistry panel development after expression profiling of human cancers
AbstractBetensky, R. A., Nutt, C. L., Batchelor, T. T., & Louis, D. N. (n.d.).Publication year
2005Journal title
Journal of Molecular DiagnosticsVolume
7Issue
2Page(s)
276-282AbstractIn recent years there have been a number of microarray expression studies in which different types of tumors were classified by identifying a panel of differentially expressed genes. Immunohistochemistry is a practical and robust method for extending gene expression data to common pathological specimens with the advantage of being applicable to paraffin-embedded tissues. However, the number of assays required for successful immunohistochemical classification remains unclear. We propose a simulation-based method for assessing sample size for an immunohistochemistry investigation after a promising gene expression study of human tumors. The goals of such an immunohistochemistry study would be to develop and validate a marker panel that yields improved prognostic classification of cancer patients. We demonstrate how the preliminary gene expression data, coupled with certain realistic assumptions, can be used to estimate the number of immunohistochemical assays required for development These assumptions are more tenable than alternative assumptions that would be required for crude analytic sample size calculations and that may yield underpowered and inefficient studies. We applied our methods to the design of an immunohistochemistry study for glioma classification and estimated the number of assays required to ensure satisfactory technical and prognostic validation. Simulation approaches for computing power and sample size that are based on existing gene expression data provide a powerful tool for efficient design of follow-up genomic studies.Testing quasi-independence of failure and truncation times via conditional kendall's tau
AbstractMartin, E. C., & Betensky, R. A. (n.d.).Publication year
2005Journal title
Journal of the American Statistical AssociationVolume
100Issue
470Page(s)
484-492AbstractTruncated survival data arise when the failure time is observed only if it falls within a subject-specific truncating set. Most analysis methods rely on the key assumption of quasi-independence, that is, factorization of the joint density of failure and truncation times into a product proportional to the individual densities in the observable region. Unlike independence of failure time and censoring time, quasi-independence can be tested. Tests of quasi-independence are available for one-sided truncation and for truncation that depends on a measured covariate, but not for more complex truncation schemes. Here tests of quasi-independenee based on a multivariate conditional Kendall's tau are proposed for doubly truncated data, bivariate left-truncated data, and other forms of truncated survival data that arise when initiating or terminating event times are interval-censored. Asymptotic properties under the null are derived. The tests are illustrated using several real datasets and evaluated via simulation.Tests for treatment group differences in the hazards for survival, before and after the occurrence of an intermediate event
AbstractBebchuk, J. D., & Betensky, R. A. (n.d.).Publication year
2005Journal title
Statistics in MedicineVolume
24Issue
3Page(s)
359-378AbstractIn many settings, one would expect that the hazard for a terminal event would change with the occurrence of an intermediate event. For example, in an AIDS clinical trial, it is of interest to assess whether there is a difference between treatments in the hazards for death prior to drop in Karnofsky performance score and in the hazards subsequent to the drop in Karnofsky score. Tests for the effect of treatment on these hazard functions, separately or jointly, are useful in conjunction with tests of overall survival. We consider four Cox regression models for the hazard function, constructed by allowing for various combinations of time-dependent stratification and time-dependent covariates, both of which are based on the occurrence of the intermediate event. Assuming a Markov transition model from the intermediate to the terminal event, partial likelihoods can be used for inference, enabling the use of standard statistical software for computation. We develop analytic approximations for the power of the derived score tests for treatment differences in the hazard functions and evaluate them through simulations. We apply our results to AIDS Clinical Trials Group (ACTG) protocol 021.Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS
AbstractFerrante, K. L., Shefner, J., Zhang, H., Betensky, R., O’Brien, M., Yu, H., Fantasia, M., Taft, J., Beal, M. F., Traynor, B., Newhall, K., Donofrio, P., Caress, J., Ashburn, C., Freiberg, B., O’Neill, C., Paladenech, C., Walker, T., Pestronk, A., … Cudkowicz, M. (n.d.).Publication year
2005Journal title
NeurologyVolume
65Issue
11Page(s)
1834-1836AbstractAn open-label dose-escalation trial was performed to assess the safety and tolerability of high doses of coenzyme Q10 (CoQ10) in ALS. CoQ10, a cofactor in mitochondrial electron transfer, may improve the mitochondrial dysfunction in ALS. In this study, CoQ10 was safe and well tolerated in 31 subjects treated with doses as high as 3,000 mg/day for 8 months.YKL-40 is a differential diagnostic marker for histologic subtypes of high-grade gliomas
AbstractNutt, C. L., Betensky, R. A., Brower, M. A., Batchelor, T. T., Louis, D. N., & Stemmer-Rachamimov, A. O. (n.d.).Publication year
2005Journal title
Clinical Cancer ResearchVolume
11Issue
6Page(s)
2258-2264AbstractPurpose and Experimental Design: In modern neurooncology, no variable affects therapeutic decisions and prognostic estimation more than tumor classification. We showed recently that class prediction models, based on gene expression profiles, classify diagnostically challenging malignant gliomas in a manner that better correlates with clinical outcome than standard pathology. In the present study, we used immunohistochemistry to investigate YKL-40 protein expression in independent sets of glioblastomas and anaplastic oligodendrogliomas to determine whether this single marker can aid classification of these high-grade gliomas. Results and Conclusions: Glioblastomas show strikingly more YKL-40 expression than anaplastic oligodendrogliomas. Only 2 of 37 glioblastomas showed completely negative YKL-40 staining in both tumor cells and extracellular matrix, whereas 18 of 29 anaplastic oligodendrogliomas were completely negative in non-microgemistocytic tumor cells and extracellular matrix. Tumor cell staining intensity was also markedly different: 84% of glioblastomas showed strong staining intensities of 2+ or 3+ whereas 76% of anaplastic oligodendrogliomas either did not stain or stained at only 1+. YKL-40 staining provided a better class distinction of glioblastoma versus anaplastic oligodendroglioma than glial fibrillary acidic protein, the current standard immunohistochemical marker used to distinguish diagnostically challenging gliomas. Moreover, a combination of YKL-40 and glial fibrillary acidic protein immunohistochemistry afforded even greater diagnostic accuracy in anaplastic oligodendrogliomas.Age-Dependent Prognostic Effects of Genetic Alterations in Glioblastoma
AbstractBatchelor, T. T., Betensky, R. A., Esposito, J. M., Pham, L. D. D., Dorfman, M. V., Piscatelli, N., Jhung, S., Rhee, D., & Louis, D. N. (n.d.).Publication year
2004Journal title
Clinical Cancer ResearchVolume
10Issue
1Page(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. A., 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. A., 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. A. (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. A., & 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 (<3%). Nevertheless, this information may be germane to the interpretation and reporting of marginally positive HCII test values.Treatment of relapsed central nervous system lymphoma with high-dose methotrexate
AbstractPlotkin, S. R., Betensky, R. A., 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. A., 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. A., 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. A., & 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. A., 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. A. (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. A., & 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. A., & 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 of <5 cm, gross total resection of the tumor, and younger age were favorable prognostic variables.Neurolymphomatosis
AbstractBaehring, J. M., Damek, D., Martin, E. C., Betensky, R. A., & 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. A., Daley, J., Zinner, M. J., Greenfield, L. J., & Rhodes, R. S. (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. A., 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
AbstractArboleda-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. A., 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"
AbstractSasaki, 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.