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
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 DermatologyAbstractBackground: 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)
659-662Early 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.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.Platelet Function Is Associated With Dementia Risk in the Framingham Heart Study
AbstractRamos-Cejudo, J., Johnson, A. D., Beiser, A., Seshadri, S., Salinas, J., Berger, J. S., Fillmore, N. R., Do, N., Zheng, C., Kovbasyuk, Z., Ardekani, B. A., Nunzio, P., Bubu, O. M., Parekh, A., Convit, A., Betensky, R. A., Wisniewski, T. M., & Osorio, R. S. (n.d.).Publication year
2022Journal title
Journal of the American Heart AssociationVolume
11Issue
9AbstractBACKGROUND: Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. METHODS AND RESULTS: We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0 years; 57.5% women). During follow-up (median, 20.5 years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0 µmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1 µmol/L epinephrine. CONCLUSIONS: Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.Sex and Race Differences in the Evaluation and Treatment of Young Adults Presenting to the Emergency Department With Chest Pain
AbstractBanco, D., Chang, J., Talmor, N., Wadhera, P., Mukhopadhyay, A., Lu, X., Dong, S., Lu, Y., Betensky, R. A., Blecker, S., Safdar, B., & Reynolds, H. R. (n.d.).Publication year
2022Journal title
Journal of the American Heart AssociationVolume
11Issue
10AbstractBACKGROUND: Acute myocardial infarctions are increasingly common among young adults. We investigated sex and racial differences in the evaluation of chest pain (CP) among young adults presenting to the emergency department. METHODS AND RESULTS: Emergency department visits for adults aged 18 to 55 years presenting with CP were identified in the National Hospital Ambulatory Medical Care Survey 2014 to 2018, which uses stratified sampling to produce national estimates. We evaluated associations between sex, race, and CP management before and after multivariable adjustment. We identified 4152 records representing 29 730 145 visits for CP among young adults. Women were less likely than men to be triaged as emergent (19.1% versus 23.3%, respectively, P<0.001), to undergo electrocardiography (74.2% versus 78.8%, respectively, P=0.024), or to be admitted to the hospital or observation unit (12.4% versus 17.9%, respectively, P<0.001), but ordering of cardiac biomarkers was similar. After multivariable adjustment, men were seen more quickly (hazard ratio [HR], 1.15 [95% CI, 1.05–1.26]) and were more likely to be admitted (adjusted odds ratio, 1.40 [95% CI, 1.08–1.81]; P=0.011). People of color waited longer for physician evaluation (HR, 0.82 [95% CI, 0.73–0.93]; P<0.001) than White adults after multivariable adjustment, but there were no racial differences in hospital admission, triage level, electrocardiography, or cardiac biomarker testing. Acute myocardial infarction was diagnosed in 1.4% of adults in the emergency department and 6.5% of admitted adults. CONCLUSIONS: Women and people of color with CP waited longer to be seen by physicians, independent of clinical features. Women were independently less likely to be admitted when presenting with CP. These differences could impact downstream treatment and outcomes.Transformation model based regression with dependently truncated and independently censored data
AbstractQian, J., Chiou, S. H., & Betensky, R. A. (n.d.).Publication year
2022Journal title
Journal of the Royal Statistical Society. Series C: Applied StatisticsVolume
71Issue
2Page(s)
395-416AbstractTruncated survival data arise when the event time is observed only if it falls within a subject specific region. The conventional risk-set adjusted Kaplan–Meier estimator or Cox model can be used for estimation of the event time distribution or regression coefficient. However, the validity of these approaches relies on the assumption of quasi-independence between truncation and event times. One model that can be used for the estimation of the survival function under dependent truncation is a structural transformation model that relates a latent, quasi-independent truncation time to the observed dependent truncation time and the event time. The transformation model approach is appealing for its simple interpretation, computational simplicity and flexibility. In this paper, we extend the transformation model approach to the regression setting. We propose three methods based on this model, in addition to a piecewise transformation model that adds greater flexibility. We investigate the performance of the proposed models through simulation studies and apply them to a study on cognitive decline in Alzheimer's disease from the National Alzheimer's Coordinating Center. We have developed an R package, tranSurv, for implementation of our method.Association of APOE Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease
AbstractQian, J., Betensky, R. A., Hyman, B. T., & Serrano-Pozo, A. (n.d.).Publication year
2021Journal title
NeurologyVolume
96Issue
19Page(s)
E2414-E2428AbstractObjective: To test the hypothesis that the APOE genotype is a significant driver of heterogeneity in Alzheimer disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation. Methods: We applied novel reverse-time longitudinal models to analyze the trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores - 2 common outcome measures in AD clinical trials - in 1,102 autopsy-proven AD cases (moderate/frequent neuritic plaques and Braak tangle stage III or greater) from the National Alzheimer's Coordinating Center Neuropathology database resembling participants with mild to moderate AD in therapeutic clinical trials. Results: APOE ϵ4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOE ϵ3/ϵ3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than APOE ϵ2 carriers (1.65 points per year), whereas APOE ϵ2 vs APOE ϵ3/ϵ3 difference was not statistically significant. APOE ϵ4 carriers had ≈1.1 times faster MMSE decline than APOE ϵ3/ϵ3 carriers (-3.45 vs -3.03 points per year) and ≈1.4 times faster decline than APOE ϵ2 carriers (-2.43 points per year), whereas APOE ϵ2 carriers had ≈1.2 times slower decline than APOE ϵ3/ϵ3 carriers (-2.43 vs -3.03 points per year). These findings remained largely unchanged after controlling for the effect of AD neuropathologic changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies. Conclusion: Compared to the APOE ϵ3/ϵ3 reference genotype, the APOE ϵ2 and ϵ4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD.Comment on “Patient preference for cellulitis treatment: At-home care is preferred to hospital-based treatment”
Shaw, K. S., Karagounis, T. K., Yin, L., Gibbon, G., Betensky, R. A., Lo Sicco, K. I., & Femia, A. N. (n.d.). In Journal of the American Academy of Dermatology (1–).Publication year
2021Volume
85Issue
3Page(s)
e157-e158Concordance measures and time-dependent ROC methods
AbstractPantoja-Galicia, N., Okereke, O. I., Blacker, D., & Betensky, R. A. (n.d.).Publication year
2021Journal title
Biostatistics and EpidemiologyVolume
5Issue
2Page(s)
232-249AbstractThe receiver operating characteristic (ROC) curve displays sensitivity versus 1-specificity over a set of thresholds. The area under the ROC curve (AUC) is a global scalar summary of this curve. In the context of time-dependent ROC methods, we are interested in global scalar measures that summarize sequences of time-dependent AUCs over time. The concordance probability is a candidate for such purposes. The concordance probability can provide a global assessment of the discrimination ability of a test for an event that occurs at random times and may be right censored. If the test adequately differentiates between subjects who survive longer times and those who survive shorter times, this will assist clinical decisions. In this context, the concordance probability may support the assessment of precision medicine tools based on prognostic biomarkers models for overall survival. Definitions of time-dependent sensitivity and specificity are reviewed. Some connections between such definitions and concordance measures are also reviewed and we establish new connections via new measures of global concordance. We explore the relationship between such measures and their corresponding time-dependent AUC. To illustrate these concepts, an application in the context of Alzheimer's disease is presented.COVID-19 in Individuals Treated With Long-Term Hydroxychloroquine: A Propensity Score-Matched Analysis of Cicatricial Alopecia Patients
AbstractShaw, K. S., Yin, L., Shah, J. K., Sally, R. A., Svigos, K. S., Adotama, P. U., Tuan, H. H., Shapiro, J., Betensky, R. A., & Lo Siccoa, K. I. (n.d.).Publication year
2021Journal title
Journal of Drugs in DermatologyVolume
20Issue
8Page(s)
914-916AbstractEarly in the COVID-19 pandemic, anti-malarial agent hydroxychloroquine (HCQ) was touted as a potentially effective COVID-19 treatment due to its purported antiinflammatory and antiviral effects.Defining the Lowest Threshold for Amyloid-PET to Predict Future Cognitive Decline and Amyloid Accumulation
AbstractFarrell, M. E., Jiang, S., Schultz, A. P., Properzi, M. J., Price, J. C., Becker, J. A., Jacobs, H. I., Hanseeuw, B. J., Rentz, D. M., Villemagne, V. L., Papp, K. V., Mormino, E. C., Betensky, R. A., Johnson, K. A., Sperling, R. A., & Buckley, R. F. (n.d.).Publication year
2021Journal title
NeurologyVolume
96Issue
4Page(s)
E619-E631AbstractIntroductionAs clinical trials move toward earlier intervention, we sought to redefine the β-amyloid (Aβ)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aβ accumulation and cognitive decline in 3 independent samples of clinically normal individuals.MethodsSequential Aβ cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aβ-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356).ResultsWithin samples, cutoffs derived from future Aβ-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5).DiscussionThese optimized thresholds can help to inform future research and clinical trials targeting early Aβ. Threshold convergence raises the possibility of contemporaneous early changes in Aβ and cognition.Classification of EvidenceThis study provides Class II evidence that among clinically normal individuals a specific Aβ-PET threshold is predictive of cognitive decline.Displaying survival of patient groups defined by covariate paths: Extensions of the Kaplan-Meier estimator
AbstractJay, M., & Betensky, R. A. (n.d.).Publication year
2021Journal title
Statistics in MedicineVolume
40Issue
8Page(s)
2024-2036AbstractExtensions of the Kaplan-Meier estimator have been developed to illustrate the relationship between a time-varying covariate of interest and survival. In particular, Snapinn et al and Xu et al developed estimators to display survival for patients who always have a certain value of a time-varying covariate. These estimators properly handle time-varying covariates, but their clinical interpretation is limited. It is of greater clinical interest to display survival for patients whose covariates lie along certain defined paths. In this article, we propose extensions of Snapinn et al and Xu et al's estimators, providing crude and covariate-adjusted estimates of the survival function for patients defined by covariate paths. We also derive analytical variance estimators. We demonstrate the utility of these estimators with medical examples and a simulation study.