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
Measures of follow-up in time-to-event studies: Why provide them and what should they be?
AbstractBetensky, R. A. (n.d.).Publication year
2015Journal title
Clinical TrialsVolume
12Issue
4Page(s)
403-408AbstractBackground/Aims: There is some consensus among authors of reports of clinical studies that a measure of follow-up time is informative for the interpretation of the Kaplan-Meier estimate of the survivor function of the event time of interest. Previous authors have suggested that length of follow-up is important to report because the findings of a study should be extracted from the time frame in which most of the subjects have had the event or have remained under observation. This time frame is where the Kaplan-Meier estimate is most stable. This concept of stability is relative to the potential maximum information about the event time distribution contained in the sample; it is not relative to the true, population survivor function. A measure of stability is useful for the interpretation of an interim analysis in which an immature survivor function is presented. Our interest in this article lies in characterizing the unobserved, complete follow-up Kaplan-Meier estimate based on the observed, partial follow-up estimate. Our focus is not on characterizing the true event time distribution relative to its estimate. The concept of stability has not been well-defined in the literature, which has led to inconsistency and lack of transparency across trials in their attempts to capture it through a variety of measures of follow-up. Methods: We report the results of a survey of recent literature on cancer clinical trials and summarize whether follow-up is reported and if so, whether it is well-defined. We define commonly used measures of follow-up in clinical studies. Results: We explain how each measure should be assessed to evaluate the stability of the Kaplan-Meier estimate for the event, and we identify relationships among measures. We propose a new measure that better conveys the desired information about the stability of the current Kaplan-Meier estimate relative to one based on complete follow-up. We apply the proposed measure to a meningioma study for illustration. Conclusion: It is useful for reports of clinical studies to supplement Kaplan-Meier estimates with quantitative assessments of the stability of those estimates relative to the potential follow-up of study participants. We justify the use of one commonly used measure, and we propose a new measure that most directly accomplishes this goal.Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma
AbstractTaylor, J. W., Dietrich, J., Gerstner, E. R., Norden, A. D., Rinne, M. L., Cahill, D. P., Stemmer-Rachamimov, A., Wen, P. Y., Betensky, R. A., Giorgio, D. H., Snodgrass, K., Randall, A. E., Batchelor, T. T., & Chi, A. S. (n.d.).Publication year
2015Journal title
Journal of Neuro-OncologyVolume
121Issue
3Page(s)
557-563AbstractTumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7–9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.Power and sample size calculations for the Wilcoxon-Mann-Whitney test in the presence of death-censored observations
AbstractMatsouaka, R. A., & Betensky, R. A. (n.d.).Publication year
2015Journal title
Statistics in MedicineVolume
34Issue
3Page(s)
406-431AbstractWe consider a clinical trial of a potentially lethal disease in which patients are randomly assigned to two treatment groups and are followed for a fixed period of time; a continuous endpoint is measured at the end of follow-up. For some patients; however, death (or severe disease progression) may preclude measurement of the endpoint. A statistical analysis that includes only patients with endpoint measurements may be biased. An alternative analysis includes all randomized patients, with rank scores assigned to the patients who are available for the endpoint measurement on the basis of the magnitude of their responses and with 'worst-rank' scores assigned to those patients whose death precluded the measurement of the continuous endpoint. The worst-rank scores are worse than all observed rank scores. The treatment effect is then evaluated using the Wilcoxon-Mann-Whitney test. In this paper, we derive closed-form formulae for the power and sample size of the Wilcoxon-Mann-Whitney test when missing measurements of the continuous endpoints because of death are replaced by worst-rank scores. We distinguish two approaches for assigning the worst-rank scores. In the tied worst-rank approach, all deaths are weighted equally, and the worst-rank scores are set to a single value that is worse than all measured responses. In the untied worst-rank approach, the worst-rank scores further rank patients according to their time of death, so that an earlier death is considered worse than a later death, which in turn is worse than all measured responses. In addition, we propose four methods for the implementation of the sample size formulae for a trial with expected early death. We conduct Monte Carlo simulation studies to evaluate the accuracy of our power and sample size formulae and to compare the four sample size estimation methods.Recognizing the problem of delayed entry in time-to-event studies: Better late than never for clinical neuroscientists
AbstractBetensky, R. A., & Mandel, M. (n.d.).Publication year
2015Journal title
Annals of NeurologyVolume
78Issue
6Page(s)
839-844AbstractEditor's Note One of the greatest differences I encountered in moving from being Editor-in-Chief of a basic science journal to the same position at Annals of Neurology was the much greater importance of meticulous review of the statistical treatment of data. In basic science, the conditions of an experiment can be set up by the investigator so that relatively simple statistical treatments can often be used with clear-cut results. Comparing the treatment and outcomes of human studies is much messier. Humans have a history before the study started; they have lives that often cause them to deviate from the protocol; and it is much harder to measure the outcomes because our methods have to be so much less invasive than they can be in animal studies. In addition, unlike mice or rats, which are deliberately inbred in a laboratory to minimize variation between animals, we are a wild species with enormous genetic and environmental variability. We solved the problem of the lack of statistical sophistication of the scientific editors by bringing in an expert in study design and statistical analysis, Dr Rebecca Betensky, a Professor of Biostatistics at the Harvard T. H. Chan School of Public Health, who serves as our Statistical Editor. We have weekly editorial conferences where the Associate Editors, Rebecca, and I consider which of the papers that were reviewed in the previous week should be published. Each week, it seems, we are treated to a private tutorial (sometimes more than one) on the complexities of study design and statistical analysis in the papers we are considering. I have learned a great deal at these meetings and thought that this education should be extended to our readers, and so I have prevailed upon Dr Betensky to address some recurring topics in our editorial conferences. We begin this month with the concept of delayed entry, a common problem in human studies that many investigators and reviewers fail to take into account. We have decided to publish this series under the NeuroGenesis section of the Annals, because this section is devoted to the career development of neurologists, and it seems critical to the professional judgment of every academic neurologist to assimilate the concepts in this series, both to improve our own work and to evaluate the work of other neurologists more critically. - C.B.S.Reductions in red blood cell 2,3-diphosphoglycerate concentration during continuous renal replacment therapy
AbstractSharma, S., Sharma, S., Brugnara, C., Betensky, R. A., & Waikar, S. S. (n.d.).Publication year
2015Journal title
Clinical Journal of the American Society of NephrologyVolume
10Issue
1Page(s)
74-79AbstractBackground and objectivesHypophosphatemia is a frequent complication during continuous renal replacement therapy (CRRT), a dialytic technique used to treat AKI in critically ill patients. This study sought to confirm that phosphate depletion during CRRT may decrease red blood cell (RBC) concentration of 2,3-diphosphoglycerate (2,3-DPG), a crucial allosteric effector of hemoglobin’s (Hgb’s) affinity for oxygen, thereby leading to impaired oxygen delivery to peripheral tissuesDesign, setting, participants, & measurementsPhosphate mass balance studies were performed in 20 patients with severe AKI through collection of CRRT effluent. RBC concentrations of 2,3-DPG, venous blood gas pH, and oxygen partial pressure required for 50% hemoglobin saturation (P50) were measured at CRRT initiation and days 2, 4, and 7. Similar measurements were obtained on days 0 and 2 in a reference group of 10 postsurgical patients, most of whom did not have AKI. Associations of 2,3-DPG with laboratory parameters and clinical outcomes were examined using mixed-effects and Cox regression modelsResultsMean 2,3-DPG levels decreased from a mean (±SD) of 13.4±3.4µmol/g Hgb to 11.0±3.1µmol/g Hgb after 2 days of CRRT (P<0.001). Mean hemoglobin saturation P50 levels decreased from 29.7±4.4 mmHg to 26.7±4.0 mmHg (P<0.001). No significant change was seen in the reference group. 2,3-DPG levels after 2 days of CRRT were not significantly lower than those in the reference group on day 2. Among patients receiving CRRT, 2,3-DPG decreased by 0.53µmol/g Hgb per 1 g phosphate removed (95% confidence interval 0.38 to 0.68µmol/g Hgb;P<0.001). Greater reductions in 2,3-DPG were associated with higher risk for death (hazard ratio, 1.43; 95% confidence interval, 1.09 to 1.88;P=0.01)ConclusionsCRRT-induced phosphate depletion is associated with measurable reductions in RBC 2,3-DPG concentration and a shift in the O2:Hgb affinity curve even in the absence of overt hypophosphatemia. 2,3-DPG reductions may be associated with higher risk for in-hospital death and represent a potentially avoidable complication of CRRT.Research participant compensation: A matter of statistical inference as well as ethics
AbstractSwanson, D. M., & Betensky, R. A. (n.d.).Publication year
2015Journal title
Contemporary Clinical TrialsVolume
45Page(s)
265-269AbstractThe ethics of compensation of research subjects for participation in clinical trials has been debated for years. One ethical issue of concern is variation among subjects in the level of compensation for identical treatments. Surprisingly, the impact of variation on the statistical inferences made from trial results has not been examined. We seek to identify how variation in compensation may influence any existing dependent censoring in clinical trials, thereby also influencing inference about the survival curve, hazard ratio, or other measures of treatment efficacy. In simulation studies, we consider a model for how compensation structure may influence the censoring model. Under existing dependent censoring, we estimate survival curves under different compensation structures and observe how these structures induce variability in the estimates. We show through this model that if the compensation structure affects the censoring model and dependent censoring is present, then variation in that structure induces variation in the estimates and affects the accuracy of estimation and inference on treatment efficacy. From the perspectives of both ethics and statistical inference, standardization and transparency in the compensation of participants in clinical trials are warranted.The influence of vascular risk factors and stroke on cognition in late life analysis of the NACC cohort
AbstractViswanathan, A., Macklin, E. A., Betensky, R., Hyman, B., Smith, E. E., & Blacker, D. (n.d.).Publication year
2015Journal title
Alzheimer disease and associated disordersVolume
29Issue
4Page(s)
287-293AbstractObjective: Vascular risk factors in mid-life predict late life cognitive decline in previously normal populations. We sought to investigate the contribution of vascular risk factors in late life to cognitive decline in a cohort of normal elderly individuals. Methods: Cognitively normal subjects were identified from the longitudinal cohort of participants in the National Alzheimer Coordinating Center (NACC) database (n=2975). The association between a composite score of vascular risk factors (based on the Framingham Stroke Risk Profile) and cognitive function was tested at baseline visit and estimated in longitudinal analyses using linear mixed-effects models. Results: Total vascular risk factor burden was associated with worse cognitive performance at baseline and faster decline longitudinally in univariate analyses but only with worse WAIS digit symbol performance in cross-sectional (estimate=-0.266 units/1 unit of Framingham Stroke Risk Profile Score; 95% confidence interval,-0.380 to-0.153; P<0.001) and longitudinal (estimate=-0.034 units/1 unit of Framingham Stroke Risk Profile Score/year; 95% confidence interval,-0.055 to-0.012; P=0.002) analyses after adjusting for age, education, and APOE genotype. Individuals with history of stroke performed significantly worse on the trails B, category fluency, and Boston naming tests in cross-sectional analyses and in delayed logical memory and digit span backwards in longitudinal analyses. Conclusions: Although the modified Framingham Stroke Risk Profile in late-life predicts rate of decline on selective neurocognitive measures in previously normal elderly individuals, age appears to be the strongest risk factor for cognitive impairment in this population. History of stroke independently influences rate of cognitive decline in these individuals.Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study
AbstractChheda, M. G., Wen, P. Y., Hochberg, F. H., Chi, A. S., Drappatz, J., Eichler, A. F., Yang, D., Beroukhim, R., Norden, A. D., Gerstner, E. R., Betensky, R. A., & Batchelor, T. T. (n.d.).Publication year
2015Journal title
Journal of Neuro-OncologyVolume
121Issue
3Page(s)
627-634AbstractTargeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease
AbstractMormino, E. C., Betensky, R. A., 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.Anatomic pattern of intracerebral hemorrhage expansion: Relation to CT angiography spot sign and hematoma center
AbstractBoulouis, G., Dumas, A., Betensky, R. A., 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; P<0.0001). Closer proximity to the spot sign was not independently associated with increased expansion in models including both terms. CONCLUSIONS - : Hemorrhages expand nonuniformly around their surface with a tendency for greater expansion closer to their center. These findings provide a novel framework for analyzing mechanisms underlying hemorrhage growth and response to treatment.Anti-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.Assumptions regarding right censoring in the presence of left truncation
AbstractQian, J., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Statistics and Probability LettersVolume
87Issue
1Page(s)
12-17AbstractClinical studies using complex sampling often involve both truncation and censoring, where there are options for the assumptions of independence of censoring and event and for the relationship between censoring and truncation. In this paper, we clarify these choices, show certain equivalences, and provide examples.Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV
AbstractGrishchuk, Y., Sri, S., Rudinskiy, N., Ma, W., Stember, K. G., Cottle, M. W., Sapp, E., Difiglia, M., Muzikansky, A., Betensky, R. A., Wong, A. M., Bacskai, B. J., Hyman, B. T., Kelleher, R. J., Cooper, J. D., & Slaugenhaupt, S. A. (n.d.).Publication year
2014Journal title
Acta Neuropathologica CommunicationsVolume
2Issue
1AbstractMucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1 -/- cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes
AbstractSabbisetti, V. S., Waikar, S. S., Antoine, D. J., Smiles, A., Wang, C., Ravisankar, A., Ito, K., Sharma, S., Ramadesikan, S., Lee, M., Briskin, ., De Jager, P. L., Ngo, T. T., Radlinski, M., Dear, J. W., Park, K. B., Betensky, R., Krolewski, A. S., & Bonventre, J. V. (n.d.).Publication year
2014Journal title
Journal of the American Society of NephrologyVolume
25Issue
10Page(s)
2177-2186AbstractCurrently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.Computationally simple estimation and improved efficiency for special cases of double truncation
AbstractAustin, M. D., Simon, D. K., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Lifetime Data AnalysisVolume
20Issue
3Page(s)
335-354AbstractDoubly truncated survival data arise when event times are observed only if they occur within subject specific intervals of times. Existing iterative estimation procedures for doubly truncated data are computationally intensive (Turnbull 38:290-295, 1976; Efron and Petrosian 94:824-825, 1999; Shen 62:835-853, 2010a). These procedures assume that the event time is independent of the truncation times, in the sample space that conforms to their requisite ordering. This type of independence is referred to as quasi-independence. In this paper we identify and consider two special cases of quasi-independence: complete quasi-independence and complete truncation dependence. For the case of complete quasi-independence, we derive the nonparametric maximum likelihood estimator in closed-form. For the case of complete truncation dependence, we derive a closed-form nonparametric estimator that requires some external information, and a semi-parametric maximum likelihood estimator that achieves improved efficiency relative to the standard nonparametric maximum likelihood estimator, in the absence of external information. We demonstrate the consistency and potentially improved efficiency of the estimators in simulation studies, and illustrate their use in application to studies of AIDS incubation and Parkinson's disease age of onset.Eliminating bias due to censoring in Kendall's tau estimators for quasi-independence of truncation and failure
AbstractAustin, M. D., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Computational Statistics and Data AnalysisVolume
73Page(s)
16-26AbstractWhile the currently available estimators for the conditional Kendall's tau measure of association between truncation and failure are valid for testing the null hypothesis of quasi-independence, they are biased when the null does not hold. This is because they converge to quantities that depend on the censoring distribution. The magnitude of the bias relative to the theoretical Kendall's tau measure of association between truncation and failure due to censoring has not been studied, and so its importance in real problems is not known. We quantify this bias in order to assess the practical usefulness of the estimators. Furthermore, we propose inverse probability weighted versions of the conditional Kendall's tau estimators to remove the effects of censoring and provide asymptotic results for the estimators. In simulations, we demonstrate the decrease in bias achieved by these inverse probability weighted estimators. We apply the estimators to the Channing House data set and an AIDS incubation data set.Evidence-based decision support for neurological diagnosis reduces errors and unnecessary workup
AbstractSegal, M. M., Williams, M. S., Gropman, A. L., Torres, A. R., Forsyth, R., Connolly, A. M., El-Hattab, A. W., Perlman, S. J., Samanta, D., Parikh, S., Pavlakis, S. G., Feldman, L. K., Betensky, R. A., & Gospe, S. M. (n.d.).Publication year
2014Journal title
Journal of Child NeurologyVolume
29Issue
4Page(s)
487-492AbstractUsing vignettes of real cases and the SimulConsult diagnostic decision support software, neurologists listed a differential diagnosis and workup before and after using the decision support. Using the software, there was a significant reduction in error, up to 75% for diagnosis and 56% for workup. This error reduction occurred despite the baseline being one in which testers were allowed to use narrative resources and Web searching. A key factor that improved performance was taking enough time (>2 minutes) to enter clinical findings into the software accurately. Under these conditions and for instances in which the diagnoses changed based on using the software, diagnostic accuracy improved in 96% of instances. There was a 6% decrease in the number of workup items accompanied by a 34% increase in relevance. The authors conclude that decision support for a neurological diagnosis can reduce errors and save on unnecessary testing.Mild to moderate Alzheimer dementia with insufficient neuropathological changes
AbstractSerrano-Pozo, A., Qian, J., Monsell, S. E., Blacker, D., Gómez-Isla, T., Betensky, R. A., Growdon, J. H., Johnson, K. A., Frosch, M. P., Sperling, R. A., & Hyman, B. T. (n.d.).Publication year
2014Journal title
Annals of NeurologyVolume
75Issue
4Page(s)
597-601AbstractRecently, ∼16% of participants in an anti-Aβ passive immunotherapy trial for mild-to-moderate Alzheimer disease (AD) had a negative baseline amyloid positron emission tomography (PET) scan. Whether they have AD or are AD clinical phenocopies remains unknown. We examined the 2005-2013 National Alzheimer's Coordinating Center autopsy database and found that ∼14% of autopsied subjects clinically diagnosed with mild-to-moderate probable AD have no or sparse neuritic plaques, which would expectedly yield a negative amyloid PET scan. More than half of these "Aβ-negative" subjects have low neurofibrillary tangle Braak stages. These findings support the implementation of a positive amyloid biomarker as an inclusion criterion in future anti-Aβ drug trials. Ann Neurol 2014;75:597-601Synergistic effect of β-amyloid and neurodegeneration on cognitive decline in clinically normal individuals
AbstractMormino, E. C., Betensky, R. A., Hedden, T., Schultz, A. P., Amariglio, R. E., Rentz, D. M., Johnson, K. A., & Sperling, R. A. (n.d.).Publication year
2014Journal title
JAMA NeurologyVolume
71Issue
11Page(s)
1379-1385AbstractIMPORTANCE: Assessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes. OBJECTIVE: To determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals. DESIGN, SETTING, AND PARTICIPANTS: Academic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women). MAIN OUTCOMES AND MEASURES: The Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ+/ND-), stage 2 (Aβ+/ND+), and suspected non-Alzheimer disease pathology (Aβ-/ND+). Cognition was assessed with a composite of neuropsychological tests administered annually. RESULTS: The Aβ+ CN individuals were more likely to be classified as ND+: 59.6%of Aβ+ CN individuals were ND+, whereas 31.9%of Aβ- CN individuals were ND+ (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04). CONCLUSIONS AND RELEVANCE: The co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses
AbstractRudinskiy, N., Hawkes, J. M., Wegmann, S., Kuchibhotla, K. V., Muzikansky, A., Betensky, R. A., Spires-Jones, T. L., & Hyman, B. T. (n.d.).Publication year
2014Journal title
Acta Neuropathologica CommunicationsVolume
2Issue
1AbstractIntraneuronal neurofibrillary tangles (NFTs) - a characteristic pathological feature of Alzheimer's and several other neurodegenerative diseases - are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.The effect of hospital care on early survival after penetrating trauma
AbstractClark, D. E., Doolittle, P. C., Winchell, R. J., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Injury EpidemiologyVolume
1Issue
1Page(s)
1-9AbstractBackground: The effectiveness of emergency medical interventions can be best evaluated using time-to-event statistical methods with time-varying covariates (TVC), but this approach is complicated by uncertainty about the actual times of death. We therefore sought to evaluate the effect of hospital intervention on mortality after penetrating trauma using a method that allowed for interval censoring of the precise times of death. Methods: Data on persons with penetrating trauma due to interpersonal assault were combined from the 2008 to 2010 National Trauma Data Bank (NTDB) and the 2004 to 2010 National Violent Death Reporting System (NVDRS). Cox and Weibull proportional hazards models for survival time (tSURV) were estimated, with TVC assumed to have constant effects for specified time intervals following hospital arrival. The Weibull model was repeated with tSURV interval-censored to reflect uncertainty about the precise times of death, using an imputation method to accommodate interval censoring along with TVC. Results: All models showed that mortality was increased by older age, female sex, firearm mechanism, and injuries involving the head/neck or trunk. Uncensored models showed a paradoxical increase in mortality associated with the first hour in a hospital. The interval-censored model showed that mortality was markedly reduced after admission to a hospital, with a hazard ratio (HR) of 0.68 (95% CI 0.63, 0.73) during the first 30 min declining to a HR of 0.01 after 120 min. Admission to a verified level I trauma center (compared to other hospitals in the NTDB) was associated with a further reduction in mortality, with a HR of 0.93 (95% CI 0.82, 0.97). Conclusions: Time-to-event models with TVC and interval censoring can be used to estimate the effect of hospital care on early mortality after penetrating trauma or other acute medical conditions and could potentially be used for interhospital comparisons.Variable importance in matched case-control studies in settings of high dimensional data
AbstractBalasubramanian, R., Andres Houseman, E., Coull, B. A., Lev, M. H., Schwamm, L. H., & Betensky, R. A. (n.d.).Publication year
2014Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
63Issue
4Page(s)
639-655AbstractSummary: We propose a method for assessing variable importance in matched case-control investigations and other highly stratified studies characterized by high dimensional data (p>>n). In simulated and real data sets, we show that the algorithm proposed performs better than a conventional univariate method (conditional logistic regression) and a popular multivariable algorithm (random forests) that does not take the matching into account. The methods are applicable to wide ranging, high impact clinical studies including metabolomic, proteomic studies and neuroimaging analyses, such as those assessing stroke and Alzheimer's disease. The methods proposed have been implemented in a freely available R library (http://cran.r-project.org/web/packages/RPCLR/index.html).Variable selection and prediction using a nested, matched case-control study: Application to hospital acquired pneumonia in stroke patients
AbstractQian, J., Payabvash, S., Kemmling, A., Lev, M. H., Schwamm, L. H., & Betensky, R. A. (n.d.).Publication year
2014Journal title
BiometricsVolume
70Issue
1Page(s)
153-163AbstractMatched case-control designs are commonly used in epidemiologic studies for increased efficiency. These designs have recently been introduced to the setting of modern imaging and genomic studies, which are characterized by high-dimensional covariates. However, appropriate statistical analyses that adjust for the matching have not been widely adopted. A matched case-control study of 430 acute ischemic stroke patients was conducted at Massachusetts General Hospital (MGH) in order to identify specific brain regions of acute infarction that are associated with hospital acquired pneumonia (HAP) in these patients. There are 138 brain regions in which infarction was measured, which introduce nearly 10,000 two-way interactions, and challenge the statistical analysis. We investigate penalized conditional and unconditional logistic regression approaches to this variable selection problem that properly differentiate between selection of main effects and of interactions, and that acknowledge the matching. This neuroimaging study was nested within a larger prospective study of HAP in 1915 stroke patients at MGH, which recorded clinical variables, but did not include neuroimaging. We demonstrate how the larger study, in conjunction with the nested, matched study, affords us the capability to derive a score for prediction of HAP in future stroke patients based on imaging and clinical features. We evaluate the proposed methods in simulation studies and we apply them to the MGH HAP study.An analysis of adaptive design variations on the sequential parallel comparison design for clinical trials
AbstractMi, M. Y., & Betensky, R. A. (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.Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in alzheimer disease
AbstractSerrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (n.d.).Publication year
2013Journal title
Journal of Neuropathology and Experimental NeurologyVolume
72Issue
6Page(s)
462-471AbstractAlthough it is clear that astrocytes and microglia cluster around dense-core amyloid plaques in Alzheimer disease (AD), whether they are primarily attracted to amyloid deposits or are just reacting to plaque-associated neuritic damage remains elusive. We postulate that astrocytes and microglia may differentially respond to fibrillar amyloid β. Therefore, we quantified the size distribution of dense-core thioflavin-S (ThioS)-positive plaques in the temporal neocortex of 40 AD patients and the microglial and astrocyte responses in their vicinity (≤50 μm) and performed correlations between both measures. As expected, both astrocytes and microglia were clearly spatially associated with ThioS-positive plaques (p = 0.0001, ≤50 μm vs >50 μm from their edge), but their relationship to ThioS-positive plaque size differed: larger ThioS-positive plaques were associated with more surrounding activated microglia (p = 0.0026), but this effect was not observed with reactive astrocytes. Microglial response to dense-core plaques seems to be proportional to their size, which we postulate reflects a chemotactic effect of amyloid β. By contrast, plaque-associated astrocytic response does not correlate with plaque size and seems to parallel the behavior of plaque-associated neuritic damage.