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
Pseudo-observations for bivariate survival data
AbstractTravis-Lumer, Y., Mandel, M., & Betensky, R. A. (n.d.).Publication year
2025Journal title
BiometricsVolume
81Issue
1AbstractThe pseudo-observations approach has been gaining popularity as a method to estimate covariate effects on censored survival data. It is used regularly to estimate covariate effects on quantities such as survival probabilities, restricted mean life, cumulative incidence, and others. In this work, we propose to generalize the pseudo-observations approach to situations where a bivariate failure-time variable is observed, subject to right censoring. The idea is to first estimate the joint survival function of both failure times and then use it to define the relevant pseudo-observations. Once the pseudo-observations are calculated, they are used as the response in a generalized linear model. We consider 2 common nonparametric estimators of the joint survival function: the estimator of Lin and Ying (1993) and the Dabrowska estimator (Dabrowska, 1988). For both estimators, we show that our bivariate pseudo-observations approach produces regression estimates that are consistent and asymptotically normal. Our proposed method enables estimation of covariate effects on quantities such as the joint survival probability at a fixed bivariate time point or simultaneously at several time points and, consequentially, can estimate covariate-adjusted conditional survival probabilities. We demonstrate the method using simulations and an analysis of 2 real-world datasets.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. A., 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 DementiaVolume
20Issue
6Page(s)
4106-4114AbstractINTRODUCTION: 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.Association of Social Determinants of Health With Brain MRI Outcomes in Individuals With Pediatric Onset Multiple Sclerosis
AbstractRoss, R., O’Neill, K. A., Betensky, R. A., Billiet, T., Kenney, R., Lovett, J. T., Maletic-Savatic, M., Meeks, H. D., Sosa, A., Waltz, M., & Krupp, L. B. (n.d.).Publication year
2024Journal title
NeurologyVolume
103Issue
12AbstractBackground and ObjectivesAccumulating evidence points to worse clinical outcomes among adults with multiple sclerosis (MS) belonging to minority or poverty-affected groups. By contrast, little is known about the outcomes of these populations with pediatric-onset MS (POMS). Individuals with POMS represent 5% of the MS population and are more racially diverse yet have been understudied regarding socioeconomic environment or characteristics. In this study, we investigated the association between childhood social determinants of health (SDOH) and brain MRI outcomes in patients with POMS.MethodsThis is a retrospective single-site cohort study of patients with POMS with brain MRI quantitatively analyzed using icobrain software to yield total white matter lesion, black hole, whole brain, white matter, and gray matter volumes. All patients with POMS evaluated at New York University Langone MS Center and who underwent high-quality volumetric MRI scans were included in this study. SDOH indicators of race, ethnicity, health insurance type, parental education, and childhood neighborhood social vulnerability index (SVI) were examined for association with MRI outcomes using linear least absolute shrinkage selection operator penalized regression modeling. Disease-modifying therapy (DMT) timing and DMT efficacy were compared for each SDOH category.ResultsA total of 138 patients with POMS (70% female) were included with a mean age of 19.86 years and median disease duration of 4 years at time of scan. Public health insurance, Black race, Hispanic ethnicity, low parental education, and high SVI (greater neighborhood disadvantage) were each associated with white matter lesion and black hole volume. SVI was the strongest individual predictor of total white matter lesion (β = 4.63, p = 0.002) and black hole volume (β = 2.91, p = 0.003). In models incorporating all SDOH variables, public health insurance was the strongest predictor of total lesion (β = 2.48, p = 0.01) and black hole volume (β = 1.50, p = 0.02), attenuating the effect of SVI (β = 1.66, p = 0.33 and β = 1.00, p = 0.39). There were no differences in DMT timing or efficacy between categories of social disadvantage.DiscussionIndividual-level and neighborhood-level indicators of social disadvantage are associated with worse brain MRI outcomes in POMS. Further investigation of race, ethnicity, and childhood disadvantage as risk factors of MS susceptibility and severity is needed to reduce MS health disparities.Autoimmune, Autoinflammatory Disease and Cutaneous Malignancy Associations with Hidradenitis Suppurativa: A Cross-Sectional Study
AbstractBrydges, H. T., Onuh, O. C., Friedman, R., Barrett, J., Betensky, R. A., Lu, C. P., Caplan, A. S., Alavi, A., & Chiu, E. S. (n.d.).Publication year
2024Journal title
American Journal of Clinical DermatologyVolume
25Issue
3Page(s)
473-484AbstractBackground: Hidradenitis suppurativa (HS) is a debilitating cutaneous disease characterized by severe painful inflammatory nodules/abscesses. At present, data regarding the epidemiology and pathophysiology of this disease are limited. Objective: To define the prevalence and comorbidity associations of HS. Methods: This was a cross-sectional study of EPICTM Cosmos© examining over 180 million US patients. Prevalences were calculated by demographic and odds ratios (OR) and identified comorbidity correlations. Results: All examined metabolism-related, psychological, and autoimmune/autoinflammatory (AI) diseases correlated with HS. The strongest associations were with pyoderma gangrenosum [OR 26.56; confidence interval (CI): 24.98–28.23], Down syndrome (OR 11.31; CI 10.93–11.70), and polycystic ovarian syndrome (OR 11.24; CI 11.09–11.38). Novel AI associations were found between HS and lupus (OR 6.60; CI 6.26–6.94) and multiple sclerosis (MS; OR 2.38; CI 2.29–2.48). Cutaneous malignancies were largely not associated in the unsegmented cohort; however, among Black patients, novel associations with melanoma (OR 2.39; CI 1.86–3.08) and basal cell carcinoma (OR 2.69; CI 2.15–3.36) were identified. Limitations: International Classification of Diseases (ICD)-based disease identification relies on coding fidelity and diagnostic accuracy. Conclusion: This is the first study to identify correlations between HS with melanoma and basal cell carcinoma (BCC) among Black patients as well as MS and lupus in all patients with HS.Comparison of comorbidities and adverse events in dermatology and rheumatology patients prescribed tofacitinib: A retrospective analysis
Needle, C. D., Klein, E. J., Gjonaj, J., Nohria, A., Karim, M., Liu, L., Shah, J., Betensky, R. A., Garshick, M., Lo Sicco, K., & Karagounis, T. K. (n.d.).Publication year
2024Journal title
Journal of the American Academy of DermatologyVolume
90Issue
3Page(s)
659-662Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline
AbstractFlaherty, R., Sui, Y. V., Masurkar, A. V., Betensky, R. A., Rusinek, H., & Lazar, M. (n.d.).Publication year
2024Journal title
Frontiers in NeurologyVolume
15AbstractIntroduction: Alzheimer’s Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent. Methods: To better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus. Results: SCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD. Discussion: The diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition.Early Detection of Amyloid-Related Changes in Memory among Cognitively Unimpaired Older Adults with Daily Digital Testing
AbstractPapp, K. V., Jutten, R. J., Soberanes, D., Weizenbaum, E., Hsieh, S., Molinare, C., Buckley, R., Betensky, R. A., Marshall, G. A., Johnson, K. A., Rentz, D. M., Sperling, R., & Amariglio, R. E. (n.d.).Publication year
2024Journal title
Annals of NeurologyVolume
95Issue
3Page(s)
507-517AbstractObjective: This study was undertaken to determine whether assessing learning over days reveals Alzheimer disease (AD) biomarker-related declines in memory consolidation that are otherwise undetectable with single time point assessments. Methods: Thirty-six (21.9%) cognitively unimpaired older adults (aged 60–91 years) were classified with elevated β-amyloid (Aβ+) and 128 (78%) were Aβ− using positron emission tomography with 11CPittsburgh compound B. Participants completed the multiday Boston Remote Assessment for Neurocognitive Health (BRANCH) for 12 min/day on personal devices (ie, smartphones, laptops), which captures the trajectory of daily learning of the same content on 3 repeated tests (Digit Signs, Groceries-Prices, Face-Name). Learning is computed as a composite of accuracy across all 3 measures. Participants also completed standard in-clinic cognitive tests as part of the Preclinical Alzheimer's Cognitive Composite (PACC-5), with 123 participants undergoing PACC-5 follow-up after 1.07 (standard deviation = 0.25) years. Results: At the cross-section, there were no statistically significant differences in performance between Aβ+/− participants on any standard in-clinic cognitive tests (eg, PACC-5) or on day 1 of multiday BRANCH. Aβ+ participants exhibited diminished 7-day learning curves on multiday BRANCH after 4 days of testing relative to Aβ− participants (Cohen d = 0.49, 95% confidence interval = 0.10–0.87). Diminished learning curves were associated with greater annual PACC-5 decline (r = 0.54, p < 0.001). Interpretation: Very early Aβ-related memory declines can be revealed by assessing learning over days, suggesting that failures in memory consolidation predate other conventional amnestic deficits in AD. Repeated digital memory assessments, increasingly feasible and uniquely able to assess memory consolidation over short time periods, have the potential to be transformative for detecting the earliest cognitive changes in preclinical AD. ANN NEUROL 2024;95:507–517.KMstability: R tools to report the stability and precision of Kaplan–Meier estimates as well as measures of follow-up in time-to-event studies
AbstractErdmann, S., & Betensky, R. (n.d.).Publication year
2024Journal title
SoftwareXVolume
26AbstractIn order to appropriately report time-to-event analyses by means of Kaplan–Meier estimates, its precision and stability should be described. The precision is often reported by confidence intervals. For reporting the stability, various measures of the follow-up time distribution are used. However, these do not provide the intended insight. Recently, a new stability measure was presented. We have developed the software KMstability for calculation and display of this stability measure, including a user-friendly R shiny application and an open-source R package. The software enables informative reporting of time-to-event analysis. This is essential for reporting time-to-event analyses at interim-analyses of clinical trials and for observational (real-world-data) studies.Pathways to personalized medicine—Embracing heterogeneity for progress in clinical therapeutics research in Alzheimer's disease
AbstractArnold, S. E., Hyman, B. T., Betensky, R. A., & Dodge, H. H. (n.d.).Publication year
2024Journal title
Alzheimer's and DementiaVolume
20Issue
10Page(s)
7384-7394AbstractBiological and clinical heterogeneity is a major challenge in research for developing new treatments for Alzheimer's disease (AD). AD may be defined by its amyloid beta and tau pathologies, but we recognize that mixed pathologies are common, and that diverse genetics, central nervous system (CNS) and systemic pathophysiological processes, and environmental/experiential factors contribute to AD's diverse clinical and neuropathological features. All these factors are rational targets for therapeutic development; indeed, there are hundreds of candidate pharmacological, dietary, neurostimulation, and lifestyle interventions that show benefits in homogeneous laboratory models. Conventional clinical trial designs accommodate heterogeneity poorly, and this may be one reason that progress in translating candidate interventions has been so difficult. We review the challenges of AD's heterogeneity for the clinical trials enterprise. We then discuss how advances in repeatable biomarkers and digital phenotyping enable novel “single-case” and adaptive trial designs to accelerate therapeutics development, moving us closer to personalized research and medicine for AD. Highlights: Alzheimer's disease is diverse in its clinical features, course, risks, and biology. Typical randomized controlled trials are exclusive and necessarily large to attain arm comparability with broad outcomes. Repeated blood biomarkers and digital tracking can improve outcome measure precision and sensitivity. This enables the use of novel “single-case” and adaptive trial designs for inclusivity, rigor, and efficiency.Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study
AbstractVernetti, P. M., Norcliffe-Kaufmann, L., Palma, J. A., Biaggioni, I., Shibao, C. A., Peltier, A., Freeman, R., Gibbons, C., Goldstein, D. S., Low, P. A., Singer, W., Coon, E. A., Miglis, M. G., Wenning, G. K., Fanciulli, A., Vernino, S., Betensky, R. A., & Kaufmann, H. (n.d.).Publication year
2024Journal title
BrainVolume
147Issue
7Page(s)
2440-2448AbstractWe aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at eight centres (seven US-based and one European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson's disease (PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB and 23% to MSA). Faster phenoconversion from study enrolment to any diagnosis was associated with urinary and sexual dysfunction [hazard ratio (HR) 5.9, 95% confidence interval (CI): 1.6-22 and HR: 3.6, 95% CI: 1.1-12] followed by subtle motor signs (HR: 2.7, 95% CI: 1.2-6), trouble swallowing (HR 2.5, 95% CI: 1.4-4.5) and changes in speech (HR:2.4, 95% CI:1.1-4.8) at enrolment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95% CI: 1.1-5.9) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95% CI: 1.2-38). Patients with a younger age of PAF onset (HR: 11, 95% CI: 2.6-46), preserved olfaction (HR: 8.7, 95% CI: 1.7-45), anhidrosis (HR: 1.8, 95% CI: 1-3.1, P = 0.042) and severe urinary problems (HR 1.6, 95% CI: 1-2.5, P = 0.033) were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95% CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.Predictors for the use of systemic therapy in stage IB Mycosis fungoides
AbstractRodriguez, E., Needle, C. D., Martinez, M. J., Nohria, A., Xing, Y., Song, C., Betensky, R., Latkowski, J. A., & Adotama, P. (n.d.). In Archives of Dermatological Research (1–).Publication year
2024Volume
316Issue
6AbstractBackground: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is aprospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) inpatients with newly diagnosed mycosis fungoides (MF). Objectives: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB)staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. Methods: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centresin 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. Results: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smallerpercentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariateanalysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA,20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs.T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%,while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improvedsignificantly both in patients with responsive disease and in those with stable disease. Conclusions: Disease characteristics such as presence of plaques and FMF influence physician treatment choices,and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, futuretreatment guidelines for early-stage MF need to address these issues.The neutrophil to lymphocyte ratio associates with markers of Alzheimer’s disease pathology in cognitively unimpaired elderly people
AbstractJacobs, T., Jacobson, S. R., Fortea, J., Berger, J. S., Vedvyas, A., Marsh, K., He, T., Gutierrez-Jimenez, E., Fillmore, N. R., Gonzalez, M., Figueredo, L., Gaggi, N. L., Plaska, C. R., Pomara, N., Blessing, E., Betensky, R., Rusinek, H., Zetterberg, H., Blennow, K., … Ramos-Cejudo, J. (n.d.).Publication year
2024Journal title
Immunity and AgeingVolume
21Issue
1AbstractBackground: An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence.Trajectories of Inflammatory Markers and Post-COVID-19 Cognitive Symptoms: A Secondary Analysis of the CONTAIN COVID-19 Randomized Trial
AbstractFrontera, J. A., Betensky, R. A., Pirofski, L. A., Wisniewski, T., Yoon, H., & Ortigoza, M. B. (n.d.).Publication year
2024Journal title
Neurology: Neuroimmunology and NeuroInflammationVolume
11Issue
3AbstractBackground and ObjectivesChronic systemic inflammation has been hypothesized to be a mechanistic factor leading to post-acute cognitive dysfunction after COVID-19. However, little data exist evaluating longitudinal inflammatory markers.MethodsWe conducted a secondary analysis of data collected from the CONTAIN randomized trial of convalescent plasma in patients hospitalized for COVID-19, including patients who completed an 18-month assessment of cognitive symptoms and PROMIS Global Health questionnaires. Patients with pre-COVID-19 dementia/cognitive abnormalities were excluded. Trajectories of serum cytokine panels, D-dimer, fibrinogen, C-reactive peptide (CRP), ferritin, lactate dehydrogenase (LDH), and absolute neutrophil counts (ANCs) were evaluated over 18 months using repeated measures and Friedman nonparametric tests. The relationships between the area under the curve (AUC) for each inflammatory marker and 18-month cognitive and global health outcomes were assessed.ResultsA total of 279 patients (N = 140 received plasma, N = 139 received placebo) were included. At 18 months, 76/279 (27%) reported cognitive abnormalities and 78/279 (28%) reported fair or poor overall health. PROMIS Global Mental and Physical Health T-scores were 0.5 standard deviations below normal in 24% and 51% of patients, respectively. Inflammatory marker levels declined significantly from hospitalization to 18 months for all markers (IL-2, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, INFγ, TNFα, D-dimer, fibrinogen, ferritin, LDH, CRP, neutrophils; all p < 0.05), with the exception of IL-1β, which remained stable over time. There were no significant associations between the AUC for any inflammatory marker and 18-month cognitive symptoms, any neurologic symptom, or PROMIS Global Physical or Mental health T-scores. Receipt of convalescent plasma was not associated with any outcome measure.DiscussionAt 18 months posthospitalization for COVID-19, cognitive abnormalities were reported in 27% of patients, and below average PROMIS Global Mental and Physical Health scores occurred in 24% and 51%, respectively. However, there were no associations with measured inflammatory markers, which decreased over time.Capturing Learning Curves With the Multiday Boston Remote Assessment of Neurocognitive Health (BRANCH): Feasibility, Reliability, and Validity
AbstractWeizenbaum, E. L., Soberanes, D., Hsieh, S., Molinare, C. P., Buckley, R. F., Betensky, R. A., Properzi, M. J., Marshall, G. A., Rentz, D. M., Johnson, K. A., Sperling, R. A., Amariglio, R. E., & Papp, K. V. (n.d.).Publication year
2023Journal title
NeuropsychologyVolume
38Issue
2Page(s)
198-210AbstractObjective: Unsupervised remote digital cognitive assessment makes frequent testing feasible and allows for measurement of learning over repeated evaluations on participants’ own devices. This provides the opportunity to derive individual multiday learning curve scores over short intervals. Here, we report feasibility, reliability, and validity, of a 7-day cognitive battery from the Boston Remote Assessment for Neurocognitive Health (Multiday BRANCH), an unsupervised web-based assessment. Method: Multiday BRANCH was administered remotely to 181 cognitively unimpaired older adults using their own electronic devices. For 7 consecutive days, participants completed three tests with associative memory components (Face–Name, Groceries–Prices, Digit Signs), using the same stimuli, to capture multiday learning curves for each test. We assessed the feasibility of capturing learning curves across the 7 days. Additionally, we examined the reliability and associations of learning curves with demographics, and traditional cognitive and subjective report measures. Results: Multiday BRANCH was feasible with 96% of participants completing all study assessments; there were no differences dependent on type of device used (t = 0.71, p =.48) or time of day completed (t = −0.08, p =.94). Psychometric properties of the learning curves were sound including good test–retest reliability of individuals’ curves (intraclass correlation = 0.94). Learning curves were positively correlated with in-person cognitive tests and subjective report of cognitive complaints. Conclusions: Multiday BRANCH is a feasible, reliable, and valid cognitive measure that may be useful for identifying subtle changes in learning and memory processes in older adults. In the future, we will determine whether Multiday BRANCH is predictive of the presence of preclinical Alzheimer’s disease.Genomic and Transcriptomic Analyses of NF1-Mutant Melanoma Identify Potential Targeted Approach for Treatment
AbstractJour, G., Illa-Bochaca, I., Ibrahim, M., Donnelly, D., Zhu, K., Miera, E. V. S. D., Vasudevaraja, V., Mezzano, V., Ramswami, S., Yeh, Y. H., Winskill, C., Betensky, R. A., Mehnert, J., & Osman, I. (n.d.).Publication year
2023Journal title
Journal of Investigative DermatologyVolume
143Issue
3Page(s)
444-455.e8AbstractThere is currently no targeted therapy to treat NF1-mutant melanomas. In this study, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1 wild-type melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using The Cancer Genome Atlas data and immunohistochemistry. Digital spatial profiling with multiplex immunohistochemistry and immunofluorescence were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% of cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 than NF1 wild-type (P = 0.008), which was independently validated both in The Cancer Genome Atlas dataset (P = 0.01, P = 0.03) and with immunohistochemistry (P = 0.013, P = 0.036), respectively. Digital spatial profiling analysis showed upregulation of LY6E within the tumor cells (false discovery rate < 0.01, log2 fold change > 1), confirmed with multiplex immunofluorescence showing colocalization of LY6E in melanoma cells. The combination of MAPK/extracellular signal‒regulated kinase kinase and CDC20 coinhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-mutant cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype.Internet usage and the prospective risk of dementia: A population-based cohort study
AbstractCho, G., Betensky, R. A., & Chang, V. W. (n.d.).Publication year
2023Journal title
Journal of the American Geriatrics SocietyVolume
71Issue
8Page(s)
2419-2429AbstractBackground: Little is known about the long-term cognitive impact of internet usage among older adults. This research characterized the association between various measures of internet usage and dementia. Methods: We followed dementia-free adults aged 50–64.9 for a maximum of 17.1 (median = 7.9) years using the Health and Retirement Study. The association between time-to-dementia and baseline internet usage was examined using cause-specific Cox models, adjusting for delayed entry and covariates. We also examined the interaction between internet usage and education, race-ethnicity, sex, and generation. Furthermore, we examined whether the risk of dementia varies by the cumulative period of regular internet usage to see if starting or continuing usage in old age modulates subsequent risk. Finally, we examined the association between the risk of dementia and daily hours of usage. Analyses were conducted from September 2021 to November 2022. Results: In 18,154 adults, regular internet usage was associated with approximately half the risk of dementia compared to non-regular usage, CHR (cause-specific hazard ratio) = 0.57, 95% CI = 0.46–0.71. The association was maintained after adjustments for self-selection into baseline usage (CHR = 0.54, 95% CI = 0.41–0.72) and signs of cognitive decline at the baseline (CHR = 0.62, 95% CI = 0.46–0.85). The difference in risk between regular and non-regular users did not vary by educational attainment, race-ethnicity, sex, and generation. In addition, additional periods of regular usage were associated with significantly reduced dementia risk, CHR = 0.80, 95% CI = 0.68–0.95. However, estimates for daily hours of usage suggested a U-shaped relationship with dementia incidence. The lowest risk was observed among adults with 0.1–2 h of usage, though estimates were non-significant due to small sample sizes. Conclusions: Regular internet users experienced approximately half the risk of dementia than non-regular users. Being a regular internet user for longer periods in late adulthood was associated with delayed cognitive impairment, although further evidence is needed on potential adverse effects of excessive usage.Neuropathology-Independent Association between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum
AbstractQian, J., Zhang, Y., Betensky, R. A., Hyman, B. T., & Serrano-Pozo, A. (n.d.).Publication year
2023Journal title
Neurology: GeneticsVolume
9Issue
1AbstractBackground and ObjectivesWe previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and that this association is independent of their effects on classical ADNC and copathologies.MethodsWe analyzed APOE associations with the cognitive trajectories (Clinical Dementia Rating scale Sum of Boxes [CDR-SOB] and Mini-Mental State Examination [MMSE]) of more than 1,000 individuals from a national clinicopathologic sample who had either no, mild (sparse neuritic plaques and the Braak neurofibrillary tangle [NFT] stage I/II), or intermediate (moderate neuritic plaques and the Braak NFT stage III/IV) ADNC levels at autopsy via 2 latent classes reverse-time longitudinal modeling.ResultsCarrying the APOEϵ4 allele was associated with a faster rate of cognitive decline by both CDR-SOB and MMSE relative to APOEϵ3 homozygotes. This association remained statistically significant after adjusting for ADNC severity, comorbid pathologies, and the effects of ADNC on the slope of cognitive decline. Our modeling strategy identified 2 latent classes in which APOEϵ4 carriers declined faster than APOEϵ3 homozygotes, with latent class 1 members representing slow decliners (CDR-SOB: 76.7% of individuals, 0.195 vs 0.146 points/y in APOEϵ4 vs APOEϵ3/ϵ3; MMSE: 88.6% of individuals, -0.303 vs -0.153 points/y in APOEϵ4 vs APOEϵ3/ϵ3), whereas latent class 2 members were fast decliners (CDR-SOB: 23.3% of participants, 1.536 vs 1.487 points/y in APOEϵ4 vs APOEϵ3/ϵ3; MMSE: 11.4% of participants, -2.538 vs -2.387 points/y in APOEϵ4 vs APOEϵ3/ϵ3). Compared with slow decliners, fast decliners were more likely to carry the APOEϵ4 allele, younger at initial visit and death, more impaired at initial and last visits, and more likely to have intermediate (vs none or mild) ADNC levels, as well as concurrent Lewy bodies and hippocampal sclerosis at autopsy.DiscussionIn a large national sample selected to represent the normal aging-early AD continuum, the APOEϵ4 allele is associated with a modest but statistically significant acceleration of the cognitive decline rate even after controlling for its effects on ADNC and comorbid pathologies.Nonparametric and semiparametric estimation with sequentially truncated survival data
AbstractBetensky, R. A., Qian, J., & Hou, J. (n.d.).Publication year
2023Journal title
BiometricsVolume
79Issue
2Page(s)
1000-1013AbstractIn observational cohort studies with complex sampling schemes, truncation arises when the time to event of interest is observed only when it falls below or exceeds another random time, that is, the truncation time. In more complex settings, observation may require a particular ordering of event times; we refer to this as sequential truncation. Estimators of the event time distribution have been developed for simple left-truncated or right-truncated data. However, these estimators may be inconsistent under sequential truncation. We propose nonparametric and semiparametric maximum likelihood estimators for the distribution of the event time of interest in the presence of sequential truncation, under two truncation models. We show the equivalence of an inverse probability weighted estimator and a product limit estimator under one of these models. We study the large sample properties of the proposed estimators and derive their asymptotic variance estimators. We evaluate the proposed methods through simulation studies and apply the methods to an Alzheimer's disease study. We have developed an R package, seqTrun, for implementation of our method.Nonparametric bounds for the survivor function under general dependent truncation
AbstractQian, J., & Betensky, R. A. (n.d.).Publication year
2023Journal title
Scandinavian Journal of StatisticsVolume
50Issue
1Page(s)
327-357AbstractTruncation occurs in cohort studies with complex sampling schemes. When truncation is ignored or incorrectly assumed to be independent of the event time in the observable region, bias can result. We derive completely nonparametric bounds for the survivor function under truncation and censoring; these extend prior nonparametric bounds derived in the absence of truncation. We also define a hazard ratio function that links the unobservable region in which event time is less than truncation time, to the observable region in which event time is greater than truncation time, under dependent truncation. When this function can be bounded, and the probability of truncation is known approximately, it yields narrower bounds than the purely nonparametric bounds. Importantly, our approach targets the true marginal survivor function over its entire support, and is not restricted to the observable region, unlike alternative estimators. We evaluate the methods in simulations and in clinical applications.Simulation of New York City's Ventilator Allocation Guideline during the Spring 2020 COVID-19 Surge
AbstractWalsh, B. C., Zhu, J., Feng, Y., Berkowitz, K. A., Betensky, R. A., Nunnally, M. E., & Pradhan, D. R. (n.d.).Publication year
2023Journal title
JAMA network openVolume
6Issue
10Page(s)
E2336736AbstractImportance: The spring 2020 surge of COVID-19 unprecedentedly strained ventilator supply in New York City, with many hospitals nearly exhausting available ventilators and subsequently seriously considering enacting crisis standards of care and implementing New York State Ventilator Allocation Guidelines (NYVAG). However, there is little evidence as to how NYVAG would perform if implemented. Objectives: To evaluate the performance and potential improvement of NYVAG during a surge of patients with respect to the length of rationing, overall mortality, and worsening health disparities. Design, Setting, and Participants: This cohort study included intubated patients in a single health system in New York City from March through July 2020. A total of 20000 simulations were conducted of ventilator triage (10000 following NYVAG and 10000 following a proposed improved NYVAG) during a crisis period, defined as the point at which the prepandemic ventilator supply was 95% utilized. Exposures: The NYVAG protocol for triage ventilators. Main Outcomes and Measures: Comparison of observed survival rates with simulations of scenarios requiring NYVAG ventilator rationing. Results: The total cohort included 1671 patients; of these, 674 intubated patients (mean [SD] age, 63.7 [13.8] years; 465 male [69.9%]) were included in the crisis period, with 571 (84.7%) testing positive for COVID-19. Simulated ventilator rationing occurred for 163.9 patients over 15.0 days, 44.4% (95% CI, 38.3%-50.0%) of whom would have survived if provided a ventilator while only 34.8% (95% CI, 28.5%-40.0%) of those newly intubated patients receiving a reallocated ventilator survived. While triage categorization at the time of intubation exhibited partial prognostic differentiation, 94.8% of all ventilator rationing occurred after a time trial. Within this subset, 43.1% were intubated for 7 or more days with a favorable SOFA score that had not improved. An estimated 60.6% of these patients would have survived if sustained on a ventilator. Revising triage subcategorization, proposed improved NYVAG, would have improved this alarming ventilator allocation inefficiency (25.3% [95% CI, 22.1%-28.4%] of those selected for ventilator rationing would have survived if provided a ventilator). NYVAG ventilator rationing did not exacerbate existing health disparities. Conclusions and Relevance: In this cohort study of intubated patients experiencing simulated ventilator rationing during the apex of the New York City COVID-19 2020 surge, NYVAG diverted ventilators from patients with a higher chance of survival to those with a lower chance of survival. Future efforts should be focused on triage subcategorization, which improved this triage inefficiency, and ventilator rationing after a time trial, when most ventilator rationing occurred..APOE ε4 and late-life cognition: mediation by structural brain imaging markers
AbstractMa, 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.Association between lower body temperature and increased tau pathology in cognitively normal older adults
AbstractBlessing, E. M., Parekh, A., Betensky, R. A., Babb, J., Saba, N., Debure, L., Varga, A. W., Ayappa, I., Rapoport, D. M., Butler, T. A., De Leon, M. J., Wisniewski, T., Lopresti, B. J., & Osorio, R. S. (n.d.).Publication year
2022Journal title
Neurobiology of DiseaseVolume
171AbstractBackground: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. Methods: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. Results: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). Conclusions: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. Clinical trial number: NCT03053908.Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia
AbstractCharpignon, M. L., Vakulenko-Lagun, B., Zheng, B., Magdamo, C., Su, B., Evans, K., Rodriguez, S., Sokolov, A., Boswell, S., Sheu, Y. H., Somai, M., Middleton, L., Hyman, B. T., Betensky, R. A., Finkelstein, S. N., Welsch, R. E., Tzoulaki, I., Blacker, D., Das, S., & Albers, M. W. (n.d.).Publication year
2022Journal title
Nature communicationsVolume
13Issue
1AbstractMetformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin’s action in the brain.Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementia
AbstractFrontera, J. A., Boutajangout, A., Masurkar, A. V., Betensky, R. A., Ge, Y., Vedvyas, A., Debure, L., Moreira, A., Lewis, A., Huang, J., Thawani, S., Balcer, L., Galetta, S., & Wisniewski, T. (n.d.).Publication year
2022Journal title
Alzheimer's and DementiaVolume
18Issue
5Page(s)
899-910AbstractIntroduction: Neurological complications among hospitalized COVID-19 patients may be associated with elevated neurodegenerative biomarkers. Methods: Among hospitalized COVID-19 patients without a history of dementia (N = 251), we compared serum total tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and amyloid beta (Aβ40,42) between patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions. COVID-19 patient biomarker levels were also compared to non-COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161). Results: Admission t-tau, p-tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in non-COVID controls with MCI or AD. Discussion: Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.Nonparametric estimation of the survival distribution under covariate-induced dependent truncation
AbstractVakulenko-Lagun, B., Qian, J., Chiou, S. H., Wang, N., & Betensky, R. A. (n.d.).Publication year
2022Journal title
BiometricsVolume
78Issue
4Page(s)
1390-1401AbstractThere is often delayed entry into observational studies, which results in left truncation. In the estimation of the distribution of time-to-event from left-truncated data, standard survival analysis methods require quasi-independence between the truncation time and event time. Incorrectly assuming quasi-independence may lead to biased estimation. We address the problem of estimation of the survival distribution when dependence between the event time and its left truncation time is induced by shared covariates. We introduce propensity scores for truncated data and propose two inverse probability weighting methods that adjust for both truncation and dependence, if all of the shared covariates are measured. The proposed methods additionally allow for right censoring. We evaluate the proposed methods in simulations, conduct sensitivity analyses, and provide guidelines for use in practice. We illustrate our approach in application to data from a central nervous system lymphoma study. The proposed methods are implemented in the R package, depLT.