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
AKT activation in human glioblastomas enhances proliferation via TSC2 and S6 kinase signaling
AbstractRiemenschneider, M. J., Betensky, R., Pasedag, S. M., & Louis, D. N. (n.d.).Publication year
2006Journal title
Cancer ResearchVolume
66Issue
11Page(s)
5618-5623AbstractAberrant AKT (protein kinase B) signaling is common in many cancers, including glioblastoma. Current models suggest that AKT acts directly, or indirectly via the TSC complex, to activate the mammalian target of rapamycin (mTOR) as the main downstream mediator of AKT signaling. mTOR activation results in subsequent activation of S6K and STAT3, as well as suppression (i.e., phosphorylation) of 4E-BP1, leading to cell cycle progression and inhibition of apoptosis. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We aimed to delineate these pathways in a primarily in situ manner using immunohistochemistry in a panel of 29 glioblastomas, emphasizing the histologie distribution of molecular changes. Within individual tumors, increased expression levels of p-TSC2, p-mTOR, P-4E-BP1, p-S6K, p-S6, and p-STAT3 were found in regions defined by elevated AKT activation. However, only TSC2, S6K, and S6 activation levels correlated significantly with AKT activation and clustered together in multidimensional scaling analyses. Ki-67 proliferation indices were significantly elevated in p-AKT-overexpressing regions, whereas expression of the apoptosis marker cleaved caspase 3 was generally low and not significantly different between the regions. These findings provide the first in vivo evidence for a close correlation between AKT and TSC2 phosphorylation levels in glioblastoma. Moreover, they suggest that downstream p-AKT effects are primarily mediated by S6 kinase signaling, thus enhancing proliferation rather than inhibiting apoptosis.Alternative derivations of a rule for early stopping in favor of H0
AbstractBetensky, R. (n.d.).Publication year
2000Journal title
American StatisticianVolume
54Issue
1Page(s)
35-39AbstractIt is often desirable to stop a large clinical trial before its planned end if a null result seems inevitable. This early stopping can save considerable resources. It is especially appealing when an experimental treatment is being compared to a standard treatment. Three procedures for early stopping, all with different interpretations and derivations, are described and shown to produce identical rules for normal data and certain parameters. In some cases, this is unexpected and informative. The procedures differ in which of their parameters are adjusted from the fixed sample values to maintain the desired Type I error in this setting of multiple looks at the data.Alternative derivations of a rule for early stopping in favor of HO
AbstractBetensky, R. (n.d.).Publication year
2000Journal title
American StatisticianVolume
54Issue
1Page(s)
35-39AbstractIt is often desirable to stop a large clinical trial before its planned end if a null result seems inevitable. This early stopping can save considerable resources. It is especially appealing when an experimental treatment is being compared to a standard treatment. Three procedures for early stopping, all with different interpretations and derivations, are described and shown to produce identical rules for normal data and certain parameters. In some cases, this is unexpected and informative. The procedures differ in which of their parameters are adjusted from the fixed sample values to maintain the desired Type I error in this setting of multiple looks at the data.Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease
AbstractMormino, E. C., Betensky, R., Hedden, T., Schultz, A. P., Ward, A., Huijbers, W., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (n.d.).Publication year
2014Journal title
NeurologyVolume
82Issue
20Page(s)
1760-1767AbstractObjective: To examine whether b-amyloid (Ab) and APOE ε4 status independently contribute or interact to influence longitudinal cognitive decline in clinically normal older individuals (CN). Methods: Data from 490 CNs were aggregated across 3 observational cohort studies (Harvard Aging Brain Study, Alzheimer's Disease Neuroimaging Initiative, and Australian Imaging Biomarkers and Lifestyle Study of Ageing; median age = 75.0 years, 255 female), and the contributions of APOE ε4 and Aβ on longitudinal change over a median of 1.49 years were examined. Cognitive decline was assessed with the Mini-Mental State Examination (MMSE) and Logical Memory (immediate and delayed recall scores). Results: High Aβ participants were more likely to be APOE ε4+ than low Aβ participants. CNs who were both high Aβ and APOE ε4+ showed greater decline in Logical Memory immediate recall (p < 0.087), Logical Memory delayed recall (p < 0.024), and MMSE (p < 0.034) compared to all other groups (low Aβ/APOE ε4-, low Aβ/APOE ε4+, and high Aβ/APOE ε4-). No other pairwise contrast was significant for any cognitive measure. Conclusions: Clinically normal individuals who are APOE ε4+ and have high Aβ showed the highest cognitive decline. These results suggest that Aβ and APOE ε4 are not redundant contributors of decline in aging but rather interact to promote decline during the short follow-up period examined in this study. Longer follow-up periods will be essential to fully elucidate the influence of Alzheimer disease risk factors on cognitive decline in aging.An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials
AbstractMi, M. Y., & Betensky, R. (n.d.).Publication year
2013Journal title
Clinical TrialsVolume
10Issue
2Page(s)
207-215AbstractBackground Currently, a growing placebo response rate has been observed in clinical trials for antidepressant drugs, a phenomenon that has made it increasingly difficult to demonstrate efficacy. The sequential parallel comparison design (SPCD) is a clinical trial design that was proposed to address this issue. The SPCD theoretically has the potential to reduce the sample-size requirement for a clinical trial and to simultaneously enrich the study population to be less responsive to the placebo. Purpose Because the basic SPCD already reduces the placebo response by removing placebo responders between the first and second phases of a trial, the purpose of this study was to examine whether we can further improve the efficiency of the basic SPCD and whether we can do so when the projected underlying drug and placebo response rates differ considerably from the actual ones. Methods Three adaptive designs that used interim analyses to readjust the length of study duration for individual patients were tested to reduce the sample-size requirement or increase the statistical power of the SPCD. Various simulations of clinical trials using the SPCD with interim analyses were conducted to test these designs through calculations of empirical power. Results From the simulations, we found that the adaptive designs can recover unnecessary resources spent in the traditional SPCD trial format with overestimated initial sample sizes and provide moderate gains in power. Under the first design, results showed up to a 25% reduction in person-days, with most power losses below 5%. In the second design, results showed up to a 8% reduction in person-days with negligible loss of power. In the third design using sample-size re-estimation, up to 25% power was recovered from underestimated sample-size scenarios. Limitations Given the numerous possible test parameters that could have been chosen for the simulations, the study's results are limited to situations described by the parameters that were used and may not generalize to all possible scenarios. Furthermore, dropout of patients is not considered in this study. Conclusions It is possible to make an already complex design such as the SPCD adaptive, and thus more efficient, potentially overcoming the problem of placebo response at lower cost. Ultimately, such a design may expedite the approval of future effective treatments.An analysis of correlated multivariate binary data : Application to familial cancers of the ovary and breast
AbstractBetensky, R., & Whittemore, A. S. (n.d.).Publication year
1996Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
45Issue
4Page(s)
411-429AbstractThe association between ovarian and breast cancer, both within and between family members, is examined using pooled data from five case-control studies. The occurrences of these diseases in sisters and mothers are analysed using a quadratic exponential model, which is an extension of the model of Zhao and Prentice for correlated univariate data. An advantage of this model is that the associations between pairs of diseases and pairs of relatives, which are of primary importance, are related to simple functions of its parameters. Also, the model applies to non-randomly sampled data, such as the case-control data, because it completely specifies the joint distribution of responses. A major weakness is that it is not immediately applicable to studies of families of different sizes. None-the-less, we find it to be useful under certain conditions, such as rare diseases. Our analysis of the data suggests that the risk of ovarian cancer is highly dependent on maternal history.An examination of methods for sample size recalculation during an experiment
AbstractBetensky, R., & Tierney, C. (n.d.).Publication year
1997Journal title
Statistics in MedicineVolume
16Issue
22Page(s)
2587-2598AbstractIn designing experiments, investigators frequently can specify an important effect that they wish to detect with high power, without the ability to provide an equally certain assessment of the variance of the response. If the experiment is designed based on a guess of the variance, an under-powered study may result. To remedy this problem, there have been several procedures proposed that obtain estimates of the variance from the data as they accrue and then recalculate the sample size accordingly. One class of procedures is fully sequential in that it assesses after each response whether the current sample size yields the desired power based on the current estimate of the variance. This approach is efficient, but it is not practical or advisable in many situations. Another class of procedures involves only two or three stages of sampling and recalculates the sample size based on the observed variance at designated times, perhaps coinciding with interim efficacy analyses. The two-stage approach can result in substantial oversampling, but it is feasible in many situations, whereas the three-stage approach corrects the problem of oversampling, but is less feasible. We propose a procedure that aims to combine the advantages of both the fully sequential and the two-stage approaches. This quasi-sequential procedure involves only two stages of sampling and it applies the stopping rule from the fully sequential procedure to data beyond the initial sample which we obtain via multiple imputation. We show through simulations that when the initial sample size is substantially less than the correct sample size, the mean squared error of the final sample size calculated from the quasi-sequential procedure can be considerably less than that from the two-stage procedure. We compare the distributions of these recalculated sample sizes and discuss our findings for alternative procedures, as well.An extension of Kendall's coefficient of concordance to bivariate interval censored data
AbstractBetensky, R., & Finkelstein, D. M. (n.d.).Publication year
1999Journal title
Statistics in MedicineVolume
18Issue
22Page(s)
3101-3109AbstractNon-parametric tests of independence, as well as accompanying measures of association, are essential tools for the analysis of bivariate data. Such tests and measures have been developed for uncensored and right censored failure time data, but have not been developed for interval censored failure time data. Bivariate interval censored data arise in AIDS studies in which screening tests for early signs of viral and bacterial infection are done at clinic visits. Because of missed clinic visits, the actual times of first positive screening tests are interval censored. To handle such data, we propose an extension of Kendall's coefficient of concordance. We apply it to data from an AIDS study that recorded times of shedding of cytomegalovirus (CMV) and times of colonization of mycobacterium avium complex (MAC). We examine the performance of our proposed measure through a simulation study.An O'Brien-Fleming sequential trial for comparing three treatments
AbstractBetensky, R. (n.d.).Publication year
1996Journal title
Annals of StatisticsVolume
24Issue
4Page(s)
1765-1791AbstractWe consider a sequential procedure for comparing three treatments with the goal of ultimately selecting the best treatment. This procedure starts with a sequential test to detect an overall treatment difference and eliminates the apparently inferior treatment if this test rejects the equality of the treatments. It then proceeds with a sequential test of the remaining two treatments. We base these sequential tests on the stopping boundaries popularized by O'Brien and Fleming. Our procedure is similar in structure to that used by Siegmund in conjunction with modified repeated significance tests. We compare the performances of the two procedures via a simulation experiment. We derive analytic approximations for an error probability, the power and the expected sample size of our procedure, which we compare to simulated values. Furthermore, we propose a modification of the procedure for the comparison of a standard treatment with experimental treatments.An optimal Wilcoxon–Mann–Whitney test of mortality and a continuous outcome
AbstractMatsouaka, R. A., Singhal, A. B., & Betensky, R. (n.d.).Publication year
2018Journal title
Statistical Methods in Medical ResearchVolume
27Issue
8Page(s)
2384-2400AbstractWe consider a two-group randomized clinical trial, where mortality affects the assessment of a follow-up continuous outcome. Using the worst-rank composite endpoint, we develop a weighted Wilcoxon–Mann–Whitney test statistic to analyze the data. We determine the optimal weights for the Wilcoxon–Mann–Whitney test statistic that maximize its power. We derive a formula for its power and demonstrate its accuracy in simulations. Finally, we apply the method to data from an acute ischemic stroke clinical trial of normobaric oxygen therapy.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.Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma
AbstractBaehring, J. M., Androudi, S., Longtine, J. J., Betensky, R., Sklar, J., Foster, C. S., & Hochberg, F. H. (n.d.).Publication year
2005Journal title
CancerVolume
104Issue
3Page(s)
591-597AbstractBACKGROUND. The morphologic diagnosis of primary and metastatic intraocular lymphoma (IOL) was made difficult by the paucicellular specimens with fragile populations of lymphocytes retrieved through pars plana vitrectomy (PPV). The analysis of immunoglobulin heavy chain (IgH) gene rearrangements (AIGHR) was used as an adjunct to cytopathology and flow cytometry in systemic lymphoma. In IOL, the sensitivity and specificity of AIGHR are unknown. METHODS. The authors reviewed the clinical records of patients who underwent PPV for suspicion of IOL at the Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary (Boston, MA) between 2000 and 2002. AIGHR was performed as a routine diagnostic test on cell lysates isolated from < 0.5 mL of vitreous fluid. The authors used seminested polymerase chain reaction (PCR) with consensus primers for the VDJ-region of the IgH gene. PCR products were analyzed by polyacrylamide gel electrophoresis. RESULTS. Thirty patients (37 specimens) with chronic vitritis and 17 patients (23 specimens) with IOL were included. The specificity of vitreous fluid cytopathology, flow cytometry, and AIGHR was 1.0, and the sensitivity values were 0.24, 0.36, and 0.64, respectively. AIGHR was negative in two patients for whom cytopathology or flow cytometry revealed the diagnosis of lymphoma. Clonal IGHR was found in four specimens classified as negative for lymphoma based on cytopathology and flow cytometry. CONCLUSIONS. AIGHR supplemented cytopathology and flow cytometry to increase the diagnostic yield in IOL.Analysis of co-aggregation of cancer based on registry data
AbstractMatthews, A. G., Betensky, R., Anton-Culver, H., Bowen, D., Griffin, C., Isaacs, C., Kasten, C., Mineau, G., Nayfield, S., Schildkraut, J., Strong, L., Weber, B., & Finkelstein, D. M. (n.d.).Publication year
2006Journal title
Community GeneticsVolume
9Issue
2Page(s)
87-92AbstractObjective: An exploratory analysis of co-aggregation of cancers using registry-based data. Methods: We utilized sibships from over 18,000 families who had been recruited to the NCI-sponsored multi-institutional Cancer Genetics Network. The analysis assesses co-aggregation at the individual and family level and adjusts for ascertainment. Results: We found statistically significant familial co-aggregation of lung cancer with pancreatic (adjusted p < 0.001), prostate (adjusted p < 0.003), and colorectal cancers (adjusted p = 0.004). In addition, we found significant familial co-aggregation of pancreatic and colorectal cancers (adjusted p = 0.018), and co-aggregation of hematopoietic and (non-ovarian) gynecologic cancers (adjusted p = 0.01). Conclusion: This analysis identified familial aggregation of cancers for which a genetic component has yet to be established.Analysis of familial aggregation in the presence of varying family sizes
AbstractMatthews, A. G., Finkelstein, D. M., & Betensky, R. (n.d.).Publication year
2005Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
54Issue
5Page(s)
847-862AbstractFamily studies are frequently undertaken as the first step in the search for genetic and/or environmental determinants of disease. Significant familial aggregation of disease is suggestive of a genetic aetiology for the disease and may lead to more focused genetic analysis. Of course, it may also be due to shared environmental factors. Many methods have been proposed in the literature for the analysis of family studies. One model that is appealing for the simplicity of its computation and the conditional interpretation of its parameters is the quadratic exponential model. However, a limiting factor in its application is that it is not reproducible, meaning that all families must be of the same size. To increase the applicability of this model, we propose a hybrid approach in which analysis is based on the assumption of the quadratic exponential model for a selected family size and combines a missing data approach for smaller families with a marginalization approach for larger families. We apply our approach to a family study of colorectal cancer that was sponsored by the Cancer Genetics Network of the National Institutes of Health. We investigate the properties of our approach in simulation studies. Our approach applies more generally to clustered binary data.Analysis of familial aggregation studies with complex ascertainment schemes
AbstractMatthews, A. G., Finkelstein, D. M., & Betensky, R. (n.d.).Publication year
2008Journal title
Statistics in MedicineVolume
27Issue
24Page(s)
5076-5092AbstractFamilial aggregation studies are a common first step in the identification of genetic determinants of disease. If aggregation is found, more refined genetic studies may be undertaken. Complex ascertainment schemes are frequently employed to ensure that the sample contains a sufficient number of families with multiple affected members, as required to detect aggregation. For example, an eligibility criterion for a family might be that both the mother and daughter have disease. Adjustments must be made for ascertainment to avoid bias. We propose adjusting for complex ascertainment schemes through a joint model for the outcomes of disease and ascertainment. This approach improves upon previous simplifying assumptions regarding the ascertainment process.Anatomic pattern of intracerebral hemorrhage expansion : Relation to CT angiography spot sign and hematoma center
AbstractBoulouis, G., Dumas, A., Betensky, R., Brouwers, H. B., Fotiadis, P., Vashkevich, A., Ayres, A., Schwab, K., Romero, J. M., Smith, E. E., Viswanathan, A., Goldstein, J. N., Rosand, J., Gurol, M. E., & Greenberg, S. M. (n.d.).Publication year
2014Journal title
StrokeVolume
45Issue
4Page(s)
1154-1156AbstractBACKGROUND AND PURPOSE - : We sought to identify baseline determinants of the anatomic pattern of hematoma expansion in patients with intracerebral hemorrhage and spot sign. METHODS - : We coregistered baseline and follow-up CT scans from 15 intracerebral hemorrhage patients and measured growth at each surface node from baseline to follow-up hematoma. We analyzed the effects of proximity to the spot sign or hematoma center on distance of expansion, controlling for covariates. RESULTS - : There was substantial node-to-node variation in the extent of expansion around each hematoma surface (mean coefficient of variation for expansion distance, 0.43; 95% confidence interval, 0.39-0.48), indicating nonuniform expansion. Closer proximity to the hematoma center was independently associated with increased expansion (0.185 mm greater expansion for each 1 mm closer to the center; PAnti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis
AbstractLiao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., Culver, J. P., Betensky, R., Wozniak, D. F., Hyman, B. T., & Holtzman, D. M. (n.d.).Publication year
2014Journal title
Journal of NeuroscienceVolume
34Issue
21Page(s)
7281-7292AbstractApolipoprotein E (apoE) is the strongest known genetic risk factor for late onset Alzheimer's disease (AD). It influences amyloid-β (Aβ) clearance and aggregation, which likely contributes in large part to its role in AD pathogenesis. We recently found that HJ6.3, a monoclonal antibody against apoE, significantly reduced Aβ plaque load when given to APPswe/PS1 ΔE9 (APP/PS1) mice starting before the onset of plaque deposition. To determine whether the anti-apoE antibody HJ6.3 affects Aβ plaques, neuronal network function, and behavior in APP/PS1 mice after plaque onset, we administered HJ6.3 (10 mg/kg/week) or PBS intraperitoneally to 7-month-old APP/PS1 mice for 21 weeks. HJ6.3 mildly improved spatial learning performance in the water maze, restored resting-state functional connectivity, and modestly reduced brain Aβ plaque load. There was no effect of HJ6.3 on total plasma cholesterol or cerebral amyloid angiopathy. To investigate the underlying mechanisms of anti-apoE immunotherapy, HJ6.3 was applied to the brain cortical surface and amyloid deposition was followed over 2 weeks using in vivo imaging. Acute exposure to HJ6.3 affected the course of amyloid deposition in that it prevented the formation of new amyloid deposits, limited their growth, and was associated with occasional clearance of plaques, a process likely associated with direct binding to amyloid aggregates. Topical application of HJ6.3 for only 14 d also decreased the density of amyloid plaques assessed postmortem. Collectively, these studies suggest that anti-apoE antibodies have therapeutic potential when given before or after the onset of Aβ pathology.Antibody-mediated clearance of amyloid-β peptide from cerebral amyloid angiopathy revealed by quantitative in vivo imaging
AbstractPrada, C. M., Garcia-Alloza, M., Betensky, R., Zhang-Nunes, S. X., Greenberg, S. M., Bacskai, B. J., & Frosch, M. P. (n.d.).Publication year
2007Journal title
Journal of NeuroscienceVolume
27Issue
8Page(s)
1973-1980AbstractCerebral amyloid angiopathy (CAA) is the accumulation of amyloid-β peptide (Aβ) in the vessel wall of arteries in the brain. Because CAA is commonly associated with Alzheimer's disease (AD), characterized by parenchymal deposition of the same peptide in the form of senile plaques, there is considerable interest in the relationship of the two deposits in generating human disease. The study of CAA is of particular importance for immunotherapeutic approaches to AD, because reports of anti-Aβ immunotherapy in mice and humans have suggested that, whereas CAA appeared resistant to clearance, its response to this treatment promoted potential adverse effects, including meningoencephalitis. We used multiphoton microscopy and longitudinal imaging to monitor CAA in a mouse model of amyloid deposition to evaluate the effects of anti-Aβ passive immunotherapy. We found detectable clearance of CAA deposits within 1 week after a single administration of antibody directly to the brain, an effect that was short-lived. Chronic administration of antibody over 2 weeks led to more robust clearance without evidence of hemorrhage or other destructive changes. We found that the progressive clearance of Aβ from vessels follows distinct kinetics from what has been previously reported for clearance of plaques (parenchymal deposits of Aβ). This quantitative in vivo imaging approach directly demonstrates that CAA in a transgenic mouse model can be cleared with an optimized immunotherapy.Antidepressant exposure and long-term dementia risk in a nationwide retrospective study on US veterans with midlife major depressive disorder
AbstractRamos-Cejudo, J., Corrigan, J. K., Zheng, C., Swinnerton, K. N., Jacobson, S. R., La, J., Betensky, R., Osorio, R. S., Madanes, S., Pomara, N., Iosifescu, D., Brophy, M., Do, N. V., & Fillmore, N. R. (n.d.).Publication year
2024Journal title
Alzheimer's and DementiaAbstractINTRODUCTION: The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. METHODS: We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS: A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION: Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. Highlights: We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.APOE ε4 and late-life cognition: mediation by structural brain imaging markers
AbstractBetensky, R., Ma, Y., Sajeev, G., VanderWeele, T. J., Viswanathan, A., Sigurdsson, S., Eiriksdottir, G., Aspelund, T., Betensky, R. A., Grodstein, F., Hofman, A., Gudnason, V., Launer, L., & Blacker, D. (n.d.).Publication year
2022Journal title
European journal of epidemiologyVolume
37Issue
6Page(s)
591-601AbstractThe apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer's disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.APOE-related risk of mild cognitive impairment and dementia for prevention trials : An analysis of four cohorts
AbstractQian, J., Wolters, F. J., Beiser, A., Haan, M., Ikram, M. A., Karlawish, J., Langbaum, J. B., Neuhaus, J. M., Reiman, E. M., Roberts, J. S., Seshadri, S., Tariot, P. N., Woods, B. M., Betensky, R., & Blacker, D. (n.d.).Publication year
2017Journal title
PLoS MedicineVolume
14Issue
3AbstractBackground: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals. Methods and findings: We included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables. Conclusions: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.APOEε2 is associated with milder clinical and pathological Alzheimer disease
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Betensky, R., & Hyman, B. T. (n.d.).Publication year
2015Journal title
Annals of NeurologyVolume
77Issue
6Page(s)
917-929AbstractObjective The Alzheimer disease (AD) APOE 4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOE 2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOE 2 remain uncertain because of its relative rarity. We investigated the effects of APOE 2 and 4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients. Methods We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOE 3/ 3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination). Results Compared to APOE 3/ 3, APOE 2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOE 4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance ( 2 > 3 > 4). Mediation analysis suggests that this is largely explained through effects on pathology. Interpretation Even when adjusted for age at onset, symptom duration, and other demographic variables, APOE 2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE 3 and 4 alleles, suggesting a relative neuroprotective effect of APOE 2 in AD.Application of futility analysis to refine jitter recordings in myasthenia gravis
AbstractNarayanaswami, P., Pantoja-Galicia, N., Betensky, R., & Rutkove, S. B. (n.d.).Publication year
2012Journal title
Muscle and NerveVolume
45Issue
4Page(s)
486-491AbstractIntroduction: The current practice of single-fiber electromyography (SFEMG) requires that 20 fiber pairs with normal jitter be collected to exclude myasthenia gravis (MG). We applied principles of futility analysis from clinical trials in an attempt to reduce that requirement. Methods: We utilized conditional power futility analysis to assess the probability of an abnormal 20-pair SFEMG based on ongoing analysis of jitter as each pair is collected. Rules for early test termination in the presence of 0, 1, or 2 abnormal pairs were identified. These rules were then applied to previously collected SFEMG data. Results: SFEMG could be stopped at just 12 pairs if all are normal and at 17 pairs if 1 is abnormal. The rules successfully determined when SFEMG could be stopped in 104 of 106 (98%) studies originally reported to be normal. Conclusions: If the first 12 SFEMG pairs have normal jitter, the study can be terminated and interpreted as normal.Application of signal processing techniques for estimating regions of copy number variations in human meningioma DNA
AbstractStamoulis, C., Betensky, R., Mohapatra, G., & Louis, D. N. (n.d.).Publication year
2009Page(s)
6973-6976AbstractWe applied mode-decomposition and matched-filtering, both signal processing techniques used to increase the signal-to-noise ratio (SNR), to array CGH data of human meningioma DNA, in order to extract genomic regions of copy-number changes potentially associated with tumor progression. DNA segments from different chromosomes were decomposed into a small number of dominant components (modes), and low-amplitude modes were eliminated. The SNR of the entire segment was increased and it was possible to identify local changes in the data spatial structure, previously indistinguishable due to noise. We applied matched-filtering to the mode-reduced signals, using a normal DNA sequences (averaged over 50 healthy donors) as the template. The residual signals from this process were analyzed to identify disease-related copy number changes. We were able to identify distinct local changes at different chromosomes in patients with recurrent versus primary meningiomas.Approximating the distribution of maximally selected McNemar's statistics
AbstractRabinowitz, D., & Betensky, R. (n.d.).Publication year
2000Journal title
BiometricsVolume
56Issue
3Page(s)
897-902AbstractIt is common in epidemiologic analyses to summarize continuous outcomes as falling above or below a threshold. With paired data and with a threshold chosen without reference to the outcomes, McNemar's test of marginal homogeneity may be applied to the resulting dichotomous pairs when testing for equality of the marginal distributions of the underlying continuous outcomes. If the threshold is chosen to maximize the test statistic, however, referring the resulting test statistic to the nominal χ2 distribution is incorrect; Instead, the p-value must be adjusted for the multiple comparisons. Here the distribution of a maximally selected McNemar's statistic is derived, and it is shown that an approximation due to Durbin (1985, Journal of Applied Probability 22, 99-122) may be used to estimate approximate p-values. The methodology is illustrated by an application to measurements of insulin-like growth factor-I (IGF-I)in matched prostate cancer cases and controls from the Physicians' Health Study. The results of Simulation experiments that assess the accuracy of the approximation in moderate sample sizes are reported.