Rebecca A Betensky
Chair of the Department of Biostatistics
Professor of Biostatistics
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.
AB, Mathematics, Harvard University, Cambridge, MAPhD, Statistics, Stanford University, Stanford, CA
Comparison of serum neurodegenerative biomarkers among hospitalized COVID-19 patients versus non-COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementiaFrontera, 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.
Journal titleAlzheimer's and Dementia
Page(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 bounds for the survivor function under general dependent truncationQian, J., & Betensky, R. A.
Journal titleScandinavian Journal of StatisticsAbstractTruncation 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.
Transformation model based regression with dependently truncated and independently censored dataQian, J., Chiou, S. H., & Betensky, R. A.
Journal titleJournal of the Royal Statistical Society. Series C: Applied Statistics
Page(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 DiseaseQian, J., Betensky, R. A., Hyman, B. T., & Serrano-Pozo, A.
Page(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. In Journal of the American Academy of Dermatology.
Concordance measures and time-dependent ROC methodsPantoja-Galicia, N., Okereke, O. I., Blacker, D., & Betensky, R. A.
Journal titleBiostatistics and Epidemiology
Page(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 PatientsShaw, 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.
Journal titleJournal of Drugs in Dermatology
Page(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 AccumulationFailed generating bibliography.Abstract
Page(s)e619-e631AbstractINTRODUCTION: As 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. METHODS: Sequential 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). RESULTS: Within 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). DISCUSSION: These 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 EVIDENCE: This 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 estimatorJay, M., & Betensky, R. A.
Journal titleStatistics in Medicine
Page(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.
Estimation of the censoring distribution in clinical trialsJiang, S., Swanson, D., & Betensky, R. A.
Journal titleContemporary Clinical Trials Communications
Volume23AbstractClinical studies with time to event endpoints typically report the median follow-up (i.e., censoring) time for the subjects in the trial, alongside the median time to event. The reason for this is to provide information about the opportunity for subjects in the study to experience the event of interest (Betensky, 2015 ). The median follow-up time is often calculated from the Kaplan–Meier estimate for time to censoring. In most clinical studies, the censoring time is a composite measure, defined as the minimum of time to drop-out from the study and time to administrative end of study. The time to drop-out component may or may not be observed; it is observed only if drop-out occurs before the event and the end of the study. However, the time to end of study is observed for each subject, as it is the time from entry to the study to the calendar date that is administratively set as the end of the study. It is known even for subjects who have the event prior to the end of the study. This decomposition of the censoring time into a time that is itself potentially censored and a time that is fully observed raises the interesting question of whether estimation of the censoring distribution could be improved through a decoupling of these times. We demonstrate in simulations that consideration of censoring in this way yields reduced variability under some circumstances and should be used in practice. We illustrate these concepts through application to a meningioma study.
Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvementPalma, J. A., Vernetti, P. M., Perez, M. A., Krismer, F., Seppi, K., Fanciulli, A., Singer, W., Low, P., Biaggioni, I., Norcliffe-Kaufmann, L., Pellecchia, M. T., Martí, M. J., Kim, H. J., Merello, M., Stankovic, I., Poewe, W., Betensky, R., Wenning, G., & Kaufmann, H.
Journal titleClinical Autonomic Research
Page(s)157-164AbstractPurpose: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. Methods: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. Results: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. Conclusions: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.
Mucocutaneous Manifestations of Multisystem Inflammatory Syndrome in Children during the COVID-19 PandemicYoung, T. K., Shaw, K. S., Shah, J. K., Noor, A., Alperin, R. A., Ratner, A. J., Orlow, S. J., Betensky, R. A., Shust, G. F., Kahn, P. J., & Oza, V. S.
Journal titleJAMA Dermatology
Page(s)207-212AbstractImportance: To date, no study has characterized the mucocutaneous features seen in hospitalized children with multisystem inflammatory syndrome in children (MIS-C) or the temporal association of these findings with the onset of systemic symptoms. Objective: To describe the mucocutaneous findings seen in children with MIS-C during the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City in 2020. Design, Setting, and Participants: A retrospective case series was conducted of 35 children admitted to 2 hospitals in New York City between April 1 and July 14, 2020, who met Centers for Disease Control and Prevention and/or epidemiologic criteria for MIS-C. Main Outcomes and Measures: Laboratory and clinical characteristics, with emphasis on mucocutaneous findings, of children who met criteria for MIS-C. The characterization of mucocutaneous features was verified by 2 board-certified pediatric dermatologists. Results: Twenty-five children (11 girls [44%]; median age, 3 years [range, 0.7-17 years]) were identified who met definitional criteria for MIS-C; an additional 10 children (5 girls [50%]; median age, 1.7 years [range, 0.2-15 years]) were included as probable MIS-C cases (patients met all criteria with the exception of laboratory test evidence of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection or known exposure). The results of polymerase chain reaction tests for SARS-CoV-2 were positive for 10 patients (29%), and the results of SARS-CoV-2 immunoglobulin G tests were positive for 19 patients (54%). Of the 35 patients, 29 (83%) exhibited mucocutaneous changes, with conjunctival injection (n = 21), palmoplantar erythema (n = 18), lip hyperemia (n = 17), periorbital erythema and edema (n = 7), strawberry tongue (n = 8), and malar erythema (n = 6) being the most common findings. Recognition of mucocutaneous findings occurred a mean of 2.7 days (range, 1-7 days) after the onset of fever. The duration of mucocutaneous findings varied from hours to days (median duration, 5 days [range, 0-11 days]). Neither the presence nor absence of mucocutaneous findings was significantly associated with overall disease severity. Conclusions and Relevance: In this case series of hospitalized children with suspected MIS-C during the COVID-19 pandemic, a wide spectrum of mucocutaneous findings was identified. Despite their protean and transient nature, these mucocutaneous features serve as important clues in the recognition of MIS-C.
Nonparametric estimation of the survival distribution under covariate-induced dependent truncationVakulenko-Lagun, B., Qian, J., Chiou, S. H., Wang, N., & Betensky, R. A.
Journal titleBiometricsAbstractThere 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.
Seizure risk with repetitive TMS: Survey results from over a half-million treatment sessionsTaylor, J. J., Newberger, N. G., Stern, A. P., Phillips, A., Feifel, D., Betensky, R. A., & Press, D. Z.
Journal titleBrain Stimulation
Page(s)965-973AbstractBackground: Seizures are rare during repetitive transcranial magnetic stimulation (rTMS) treatment, but estimating risk is difficult because of study heterogeneity and sampling limitations. Moreover, there are few studies comparing rates between device manufacturers. Objective: The objective of this study was to calculate rTMS seizure rates across various FDA-cleared devices in naturalistic clinical settings. Methods: In July and August 2018, approximately 500 members of the Clinical TMS Society (CTMSS) were electronically surveyed about seizures in their practices. Seizures were distinguished from non-seizures by a remote semi-structured interview with a Board-certified neurologist and Co-Chair of the CTMSS Standards Committee. Exact Poisson calculations were used to estimate seizure rates and confidence intervals across the four most widely used manufacturers. Results: The survey was completed by 134 members, with 9 responses excluded because of data inconsistencies. In total, 18 seizures were reported in 586,656 sessions and 25,526 patients across all device manufacturers. The overall seizure rate was 0.31 (95% CI: 0.18, 0.48) per 10,000 sessions, and 0.71 (95% CI: 0.42, 1.11) per 1000 patients. The Brainsway H-coil seizure rate of 5.56 per 1000 patients (95% CI: 2.77,9.95) was significantly higher (p < 0.001) than the three most widely used figure- 8 coil devices’ combined seizure rate of 0.14 per 1000 patients (95% CI: 0.01, 0.51). Conclusion: The absolute risk of a seizure with rTMS is low, but generic Brainsway H-coil treatment appears to be associated with a higher relative risk than generic figure- 8 coil treatment. Well-designed prospective studies are warranted to further investigate this risk.
The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart StudyRamos-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., Bubu, O. M., Parekh, A., Convit, A., Betensky, R. A., Wisniewski, T. M., & Osorio, R. S.
Journal titleFrontiers in Aging Neuroscience
Volume13AbstractObjective: Active neutrophils are important contributors to Alzheimer’s disease (AD) pathology through the formation of capillary stalls that compromise cerebral blood flow (CBF) and through aberrant neutrophil signaling that advances disease progression. The neutrophil to lymphocyte ratio (NLR) is a proxy of neutrophil-mediated inflammation, and higher NLR is found in persons diagnosed with clinical AD. The objective of this study was to investigate whether increased NLR in older adults is independently associated with the risk of subsequent dementia. Methods: We examined associations of baseline NLR with incident dementia risk in the community-based Framingham Heart Study (FHS) longitudinal cohorts. The association between NLR and risk of dementia was evaluated using the cumulative incidence function (CIF) and inverse probability-weighted Cox proportional cause-specific hazards regression models, with adjustment for age, sex, body mass index (BMI), systolic and diastolic blood pressure, diabetes, current smoking status, low-density lipoprotein (LDH), high-density lipoprotein (LDL), total cholesterol, triglycerides, and history of cardiovascular disease (CVD). Random forest survival models were used to evaluate the relative predictive value of the model covariates on dementia risk. Results: The final study sample included 1,648 participants with FHS (average age, 69 years; 56% women). During follow-up (median, 5.9 years), we observed 51 cases of incident dementia, of which 41 were AD cases. Results from weighted models suggested that the NLR was independently associated with incident dementia, and it was preceded in predictive value only by age, history of CVD, and blood pressure at baseline. Conclusion: Our study shows that individuals with higher NLR are at a greater risk of subsequent dementia during a 5.9-year follow-up period. Further evaluating the role of neutrophil-mediated inflammation in AD progression may be warranted.
A pilot protocol to assess the feasibility of a virtual multiple crossover, randomized controlled trial design using methylphenidate in mild cognitive impairmentDesRuisseaux, L. A., Williams, V. J., McManus, A. J., Gupta, A. S., Carlyle, B. C., Azami, H., Gerber, J. A., Bolling, A. M., Cook, C. L., Betensky, R. A., & Arnold, S. E.
Issue1AbstractBackground: The conventional clinical trial design in Alzheimer’s disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an “average” patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level (“N-of-1”) regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design. Methods: Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments. Discussion: This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research. Trial registration: ClinicalTrials.gov, NCT03811847. Registered on 21 January 2019.
Accounting for incomplete testing in the estimation of epidemic parametersBetensky, R. A., & Feng, Y.
Journal titleInternational Journal of Epidemiology
Association of anxiety with subcortical amyloidosis in cognitively normal older adultsHanseeuw, B. J., Jonas, V., Jackson, J., Betensky, R. A., Rentz, D. M., Johnson, K. A., Sperling, R. A., & Donovan, N. J.
Journal titleMolecular Psychiatry
Page(s)2599-2607AbstractLate-life anxiety has been associated with increased progression from normal cognition to amnestic MCI, suggesting that anxiety may be a neuropsychiatric symptom of Alzheimer’s disease (AD) pathological changes and a possible marker of anatomical progression in preclinical AD. This study examined whether cortical or subcortical amyloidosis, indicating earlier or later stages of preclinical AD, was associated with greater self-reported anxiety among 118 cognitively normal volunteers, aged 65–90 years, and whether this association was stronger in APOEε4 carriers. Participants underwent Pittsburgh Compound B Positron Emission Tomography (PiB-PET) to assess fibrillar amyloid-β burden in cortical and subcortical regions, and measurement of anxiety using the Hospital Anxiety and Depression Scale-anxiety subscale. Higher PiB-PET measures in the subcortex (striatum, amygdala, and thalamus), but not in the cortex, were associated with greater anxiety, adjusting for demographics, cognition, and depression. Findings were similar using a cortico-striatal staging system and continuous PET measurements. Anxiety was highest in APOEε4 carriers with subcortical amyloidosis. This work supports in vivo staging of amyloid-β deposition in both cortical and subcortical regions as a promising approach to the study of neuropsychiatric symptoms such as anxiety in cognitively normal older individuals. Elevated anxiety symptoms in combination with high-risk biological factors such as APOEε4 and subcortical amyloid-β may identify participants closest to MCI for secondary prevention trials.
Characteristics of Paid Malpractice Claims among Resident Physicians from 2001 to 2015 in the United StatesGlover, M., McGee, G. W., Wilkinson, D. S., Singh, H., Bolick, A., Betensky, R. A., Harvey, H. B., Weinstein, D., & Schaffer, A.
Journal titleAcademic Medicine
Page(s)255-262AbstractPurpose Limited information exists about medical malpractice claims against physicians-in-training. Data on residents' involvement in malpractice actions may inform perceptions about medicolegal liability and influence clinical decision-making at a formative stage. This study aimed to characterize rates and payment amounts of paid malpractice claims on behalf of resident physicians in the United States. Method Using data from the National Practitioner Data Bank, 1,248 paid malpractice claims against resident physicians (interns, residents, and fellows) from 2001 to 2015, representing 1,632,471 residents-years, were analyzed. Temporal trends in overall and specialty-specific paid claim rates, payment amounts, catastrophic (> $1 million) and small (< $100,000) payments, and other claim characteristics were assessed. Payment amounts were compared with attending physicians during the same time period. Results The overall paid malpractice claim rate was 0.76 per 1,000 resident-years from 2001 to 2015. Among 1,194 unique residents with paid claims, 95.7% had exactly 1 claim, while 4.3% had 2-4 claims during training. Specialty-specific paid claim rates ranged from 0.12 per 1,000 resident-years (pathology) to 2.96 (obstetrics and gynecology). Overall paid claim rates decreased by 52% from 2001-2005 to 2011-2015 (95% confidence interval [CI]: 0.45, 0.59). Median inflation-adjusted payment amount was $199,024 (2015 dollars), not significantly different from payments made on behalf of attending physicians during the same period. Proportions of catastrophic (11.2%) and small (33.1%) claims did not significantly change over the study period. Conclusions From 2001 to 2015, paid malpractice claim rates on behalf of resident physicians decreased by 52%, while median payment amounts were stable. Resident paid claim rates were lower than attending physicians, while payment amounts were similar.
Exchanging Dermatoscopes for Stethoscopes: Has the COVID-19 Pandemic Highlighted Gaps in US Dermatology Residency Training?Shaw, K. S., Karagounis, T. K., Yin, L., Svigos, K., Gibbon, G. T., Betensky, R. A., & Lo Sicco, K. I.
Journal titleJournal of Drugs in Dermatology
Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient dataThomalla, G., Boutitie, F., Ma, H., Koga, M., Ringleb, P., Schwamm, L. H., Wu, O., Bendszus, M., Bladin, C. F., Campbell, B. C., Cheng, B., Churilov, L., Ebinger, M., Endres, M., Fiebach, J. B., Fukuda-Doi, M., Inoue, M., Kleinig, T. J., Latour, L. L., Lemmens, R., Levi, C. R., Leys, D., Miwa, K., Molina, C. A., Muir, K. W., Nighoghossian, N., Parsons, M. W., Pedraza, S., Schellinger, P. D., Schwab, S., Simonsen, C. Z., Song, S. S., Thijs, V., Toni, D., Hsu, C. Y., Wahlgren, N., Yamamoto, H., Yassi, N., Yoshimura, S., Warach, S., Hacke, W., Toyoda, K., Donnan, G. A., Davis, S. M., Gerloff, C., Acosta, B. R., Aegidius, K., Albiker, C., Alegiani, A., Almendrote, M., Alonso, A., Althaus, K., Amarenco, P., Amiri, H., Anders, B., Aniculaesei, A., Appleton, J., Arenillas, J., Back, C., Bähr, C., Bardutzky, J., Baronnet-Chauvet, F., Bathe-Peters, R., Bayer-Karpinska, A., Becerra, J. L., Beck, C., Belchí Guillamon, O., Benoit, A., Berhoune, N., Bindila, D., Birchenall, J., Blanc-Lasserre, K., Blanco Gonzales, M., Bobinger, T., Bodechtel, U., Bodiguel, E., Bojaryn, U., Bonnet, L., Bouamra, B., Bourgeois, P., Breuer, L., Breynaert, L., Broughton, D., Brouns, R., Brugirard, S., Bruneel, B., Buggle, F., Cakmak, S., Calleja, A., Calvet, D., Carrera, D., Chen, H. C., Cheripelli, B., Cho, T. H., Choe, C. U., Choy, L., Christensen, H., Ciatipis, M., Cloud, G., Cogez, J., Cortijo, E., Crozier, S., Damgaard, D., Dani, K., De Coene, B., De Hollander, I., De Keyser, J., De Klippel, N., De Maeseneire, C., De Smedt, A., Del Mar Castellanos Rodrigo, M., Deltour, S., Demeestere, J., Derex, L., Desfontaines, P., Dittrich, R., Dixit, A., Dobbels, L., Domigo, V., Dorado, L., Druart, C., Dupont, K. H., Dusart, A., Dziewas, R., Ebner, M., Edjali-Goujon, M., Eisele, P., El Tawil, S., Elhfnawy, A., Etexberria, A., Evans, N., Fandler, S., Fazekas, F., Felix, S., Fiebach, J. B., Fiehler, J., Filipov, A., Filipski, K., Fleischmann, R., Foerch, C., Ford, I., Gaenslen, A., Galinovic, I., Gancedo, E. M., Ganeshan, R., García Esperón, C., Garrido, A., Gattringer, T., Geraghty, O., Geran, R., Gerner, S., Godon-Hardy, S., Göhler, J., Golsari, A., Gomis, M., Gorriz, D., Gramse, V., Grau, L., Griebe, M., Guerrero, C., Guerzoglu, D., Guettier, S., Guiraud, V., Gumbinger, C., Gunreben, I., Haertig, F., Hametner, C., Hanseeuw, B., Hansen, A., Hansen, J., Harbo, T., Harloff, A., Harmel, P., Häusler, K. G., Heinen, F., Held, V., Hellwig, S., Hemelsoet, D., Hennerici, M., Herm, J., Hermans, S., Hernández, M., Hervas Vicente, J., Hjort, N., Hobeanu, C., Hobohm, C., Höfner, E., Hohenbichler, K., Hommel, M., Hoppe, J., Hornberger, E., Hoyer, C., Huang, X., Ipsen, N., Isern, I., Ispierto, L., Iversen, H., Jeppesen, L., Jimenez, M., Jungehülsing, J., Jüttler, E., Kalladka, D., Kallmünzer, B., Kar, A., Kellert, L., Kemmling, A., Kessler, T., Khan, U., Klein, M., Kleinschnitz, C., Klockziem, M., Knops, M., Koehler, L., Koehrmann, M., Kohlfürst, H., Kollmar, R., Kraft, P., Krause, T., Kristensen, B., Kröber, J. M., Kurka, N., Ladoux, A., Laloux, P., Lamy, C., Landrault, E., Lauer, A., Lebely, C., Leempoel, J., Lees, K., Leger, A., Legrand, L., Li, L., Löbbe, A. M., London, F., Lopez-cancio, E., Lorenz, M., Louw, S., Lovelock, C., Lozano Sánchez, M., Lucente, G., Lückl, J., Luna, A., Macha, K., Machet, A., Mackenrodt, D., Madzar, D., Majoie, C., Männer, A., Maqueda, V., Marstrand, J., Martinez, A., Marzina, A., Mechthouff, L., Meden, P., Meersman, G., Meier, J., Mellerio, C., Menn, O., Meyer, N., Michalski, D., Michels, P., Michelsen, L., Millán Torne, M., Minnerup, J., Modrau, B., Moeller, S., Møller, A., Morel, N., Moreton, F., Morin, L., Moulin, T., Moynihan, B., Mueller, A. K., Mulero, P., Mundiyanapurath, S., Mutzenbach, J., Nagel, S., Naggara, O., Nallasivan, A., Navalpotro, I., Nave, A. H., Nederkoorn, P., Neeb, L., Neugebauer, H., Neumann-Haefelin, T., Oberndorfer, S., Opherk, C., Oppel, L., Oppenheim, C., Orthgieß, J., Ostergaard, L., Paindeville, P., Palomeras, E., Panitz, V., Patel, B., Peeters, A., Peeters, D., Pellisé, A., Pelz, J., Pereira, A., Pérez De La Ossa, N., Perry, R., Petraza, S., Peysson, S., Pfeilschifter, W., Pichler, A., Pierskalla, A., Pledl, H. W., Poli, S., Pomrehn, K., Poulsen, M., Prats, L., Presas, S., Prohaska, E., Puetz, V., Puig, J., Puig Alcántara, J., Purrucker, J., Quenardelle, V., Ramachandran, S., Raphaelle, S., Raposo, N., Reiff, T., Remmers, M., Renou, P., Ribitsch, M., Richter, H., Ritter, M., Ritzenthaler, T., Rodier, G., Rodriguez-Regent, C., Rodríguez-Yáñez, M., Roennefarth, M., Roffe, C., Rosenbaum, S., Rosso, C., Röther, J., Rozanski, M., Ruiz De Morales, N., Russo, F., Rutgers, M., Sagnier, S., Samson, Y., Sánchez, J., Sauer, T., Schäfer, J. H., Schieber, S., Schill, J., Schlak, D., Schlemm, L., Schmidt, S., Schonewille, W., Schröder, J., Schulz, A., Schurig, J., Schwarting, S., Schwarz, A., Schwarzbach, C., Seidel, M., Seiler, A., Sembill, J., Serena Leal, J., Shetty, A., Sibon, I., Simonsen, C. Z., Singer, O., Sivagnanaratham, A., Smets, I., Smith, C., Soors, P., Sprigg, N., Spruegel, M., Stark, D., Steinert, S., Stösser, S., Stuermlinger, M., Swinnen, B., Tamazyan, R., Tembl, J., Terceno Izaga, M., Touze, E., Truelsen, T., Turc, G., Turine, G., Tütüncü, S., Tyrell, P., Ustrell, X., Vadot, W., Vallet, A. E., Vallet, P., Van Den Berg, L., Van Den Berg, S., Van Eendenburg, C., Van Hooff, R. J., Van Sloten, I., Vanacker, P., Vancaester, E., Vanderdonckt, P., Vandermeeren, Y., Vanhee, F., Veltkamp, R., Vestergaard, K., Viguier, A., Vilas, D., Villringer, K., Voget, D., Von Schrader, J., Von Weitzel, P., Warburton, E., Weber, C., Weber, J., Wegscheider, K., Wegscheider, M., Weimar, C., Weinstich, K., Weise, C., Weise, G., Willems, C., Winder, K., Wittayer, M., Wolf, M., Wolf, M., Wolff, V., Wollboldt, C., Wollenweber, F., Wouters, A., Yalo, B., Yger, M., Younan, N., Yperzeele, L., Zegarac, V., Zeiner, P., Ziemann, U., Zonneveld, T., Zuber, M., Akutsu, T., Aoki, J., Arakawa, S., Doijiri, R., Egashira, Y., Enomoto, Y., Furui, E., Furuta, K., Gotoh, S., Hamasaki, T., Hasegawa, Y., Hirano, T., Homma, K., Ichijyo, M., Ide, T., Igarashi, S., Iguchi, Y., Ihara, M., Ikenouchi, H., Inoue, T., Itabashi, R., Ito, Y., Iwama, T., Kamiyama, K., Kamiyoshi, S., Kanai, H., Kanematsu, Y., Kanzawa, T., Kimura, K., Kitayama, J., Kitazono, T., Kondo, R., Kudo, K., Kusumi, M., Kuwahara, K., Matsumoto, S., Matsuoka, H., Mihara, B., Minematsu, K., Miura, K., Morita, N., Mouri, W., Murata, K., Nagakane, Y., Nakase, T., Ohara, H., Ohara, N., Ohnishi, H., Ohta, H., Ohtaki, M., Ohtani, R., Ohtsuki, T., Ohyama, H., Okada, T., Okada, Y., Osaki, M., Sakai, N., Sanbongi, Y., Sasaki, N., Sasaki, M., Sato, S., Seki, K., Shimizu, W., Shiokawa, Y., Sozu, T., Suzuki, J., Suzuki, R., Takagi, Y., Takizawa, S., Tanahashi, N., Tanaka, E., Tanaka, R., Tateishi, Y., Terada, T., Terasaki, T., Todo, K., Tokunaga, A., Tsujino, A., Ueda, T., Uesaka, Y., Uotani, M., Urabe, T., Watanabe, M., Yagita, Y., Yakushiji, Y., Yasui, K., Yonehara, T., Yoshimura, S., Aarnio, K., Alemseged, F., Anderson, C., Ang, T., Archer, M. L., Attia, J., Bailey, P., Balabanski, A., Barber, A., Barber, P. A., Bernhardt, J., Bivard, A., Blacker, D., Bladin, C. F., Brodtmann, A., Cadilhac, D., Carey, L., Celestino, S., Chan, L., Chang, W. H., ChangI, A., Chen, C. H., Chen, C. I., Chen, H. F., Chen, T. C., Chen, W. H., Chen, Y. Y., Cheng, C. A., Cheong, E., Chiou, Y. W., Choi, P. M., Chu, H. J., Chuang, C. S., Chung, T. C., Churilov, L., Clissold, B., Connelly, A., Coote, S., Coulton, B., Cowley, E., Cranefield, J., Curtze, S., D’Este, C., Davis, S. M., Day, S., Desmond, P. M., Dewey, H. M., Ding, C., Drew, R., Eirola, S., Field, D., Frost, T., Garcia-Esperon, C., George, K., Gerraty, R., Grimley, R., Guo, Y. C., Hankey, G., Harvey, J., Ho, S. C., Hogan, K., Howells, D., Hsiao, P. M., Hsu, C. H., Hsu, C. T., Hsu, C. S., Hsu, J. P., Hsu, Y. D., Hsu, Y. T., Hu, C. J., Huang, C. C., Huang, H. Y., Huang, M. Y., Huang, S. C., Huang, W. S., Jackson, D., Jeng, J. S., Jiang, S. K., Kaauwai, L., Kasari, O., King, J., Koivu, M., Kolbe, J., Krause, M., Kuan, C. W., Kung, W. L., Kyndt, C., Lau, C. L., Lee, A., Lee, C. Y., Lee, J. T., Lee, Y., Lee, Y. C., Levi, C., Levi, C. R., Lien, L. M., Lim, J. C., Lin, C. C., Lin, C. H., Lin, C. M., Lin, D., Liu, C. H., Liu, J., Lo, Y. C., Loh, P. S., Low, E., Lu, C. H., Lu, C. J., Lu, M. K., Ly, J., Macaulay, L., Macdonnell, R., Mackey, E., Macleod, M., Mahadevan, J., Maxwell, V., McCoy, R., McDonald, A., McModie, S., Meretoja, A., Mishra, S., Mitchell, P. J., Miteff, F., Moore, A., Muller, C., Ng, F., Ng, F. C., Ng, J. L., O’Brian, W., O’Collins, V., Oxley, T. J., Patel, S., Peng, G. S., Pesavento, L., Phan, T., Rodrigues, E., Ross, Z., Sabet, A., Sallaberger, M., Salvaris, P., Shah, D., Sharma, G., Sibolt, G., Simpson, M., Singhal, S., Snow, B., Spratt, N., Stark, R., Sturm, J., Sun, M. C., Sun, Y., Sung, P. S., Sung, Y. F., Suzuki, M., Tan, M., Tang, S. C., Tatlisumak, T., Thijs, V., Tiainen, M., Tsai, C. H., Tsai, C. K., Tsai, C. L., Tsai, H. T., Tsai, L. K., Tseng, C. H., Tseng, L. T., Tsoleridis, J., Tu, H., Tu, H. T., Vallat, W., Virta, J., Wang, W. C., Wang, Y. T., Waters, M., Weir, L., Wijeratne, T., Williams, C., Wilson, W., Wong, A. A., Wong, K., Wu, T. Y., Wu, Y. H., Yan, B., Yang, F. C., Yang, Y. W., Yeh, H. L., Yeh, J. H., Yeh, S. J., Yen, C. H., Young, D., Ysai, C. L., Zhang, W. W., Zhao, H., Zhao, L., Althaus-Knaurer, K., Berrouschot, J., Bluhmki, E., Bovi, P., Chatellier, G., Cove, L., Davis, S., Dixit, A., Ehrenkrona, C., Eschenfelder, C., Fatar, M., Francisco Arenillas, J., Gruber, F., Kala, L., Kapeller, P., Kaste, M., Kessler, C., Köhrmann, M., Laage, R., Lees, K. R., Luna Rodriguez, A., Mas, J. L., Mikulik, R., Molina, C., Muddegowda, G., Niederkorn, K., Nuñez, X., Serena, J., Sobesky, J., Steiner, T., Svenson, A. S., Von Kummer, R., Wardlaw, J., Betensky, R. A., Boulouis, G., Carandang, R. A., Copen, W. A., Cougo, P., Cutting, S., Drake, K., Ford, A. L., Hallenbeck, J., Harris, G. J., Hoesch, R., Hsia, A., Kase, C., Latour, L., Lev, M. H., Muzikansky, A., Nagaraja, N., Schwamm, L. H., Searls, E., Song, S. S., Starkman, S., Yoo, A. J., & Zand, R.
Journal titleThe Lancet
Page(s)1574-1584AbstractBackground: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None.
Inverse probability weighting methods for Cox regression with right-truncated dataVakulenko-Lagun, B., Mandel, M., & Betensky, R. A.
Page(s)484-495AbstractRight-truncated data arise when observations are ascertained retrospectively, and only subjects who experience the event of interest by the time of sampling are selected. Such a selection scheme, without adjustment, leads to biased estimation of covariate effects in the Cox proportional hazards model. The existing methods for fitting the Cox model to right-truncated data, which are based on the maximization of the likelihood or solving estimating equations with respect to both the baseline hazard function and the covariate effects, are numerically challenging. We consider two alternative simple methods based on inverse probability weighting (IPW) estimating equations, which allow consistent estimation of covariate effects under a positivity assumption and avoid estimation of baseline hazards. We discuss problems of identifiability and consistency that arise when positivity does not hold and show that although the partial tests for null effects based on these IPW methods can be used in some settings even in the absence of positivity, they are not valid in general. We propose adjusted estimating equations that incorporate the probability of observation when it is known from external sources, which results in consistent estimation. We compare the methods in simulations and apply them to the analyses of human immunodeficiency virus latency.
Prediagnostic adult body mass index change and esophageal adenocarcinoma survivalLoehrer, E. A., Giovannucci, E. L., Betensky, R. A., Shafer, A., & Christiani, D. C.
Journal titleCancer Medicine
Page(s)3613-3622AbstractBackground: We examined whether body mass index (BMI) changes in adulthood, prior to disease onset, are associated with overall survival among esophageal adenocarcinoma patients. Methods: We included 285 histologically confirmed patients with a complete baseline BMI questionnaire. Using extended Cox regression models, we obtained adjusted hazard ratios (HRs) for the associations between overall survival and BMI at diagnosis, BMI 6 months before diagnosis, self-reported average adult BMI, and ΔBMI (BMI 6 months before diagnosis minus average adult BMI), categorized into tertiles <0 kg/m2 (BMI loss), ≥0 and <1.25 kg/m2 (stable BMI), and ≥1.25 kg/m2 (BMI gain). We also assessed interaction between ΔBMI and average adult BMI (≥ kg/m2 versus <27.5 kg/m2) with overall survival. Results: Body mass index at diagnosis >25 and <35 kg/m2 was associated with better overall survival. Compared to patients with stable BMI in adulthood, patients who gained BMI throughout adulthood had 1.68 times the all-cause hazard of death (95% CI: 1.17-2.43; P <.01), independent of diagnosis BMI and percent weight loss 6 months before diagnosis. Compared to patients with average adult BMI < 27.5 who maintained stable adult BMI, patients with average adult BMI ≥ 27.5 kg/m2 who gained BMI had the worst survival (HR = 3.05; 95% CI 1.62-5.72; P <.01). Conclusion: Body mass index gain in adulthood is associated with poor overall survival, and maintaining a normal body weight throughout adulthood is associated with the best overall survival among esophageal adenocarcinoma patients, independent of BMI at diagnosis.
Association of Amyloid and Tau with Cognition in Preclinical Alzheimer Disease: A Longitudinal StudyHanseeuw, B. J., Betensky, R. A., Jacobs, H. I., Schultz, A. P., Sepulcre, J., Becker, J. A., Cosio, D. M., Farrell, M., Quiroz, Y. T., Mormino, E. C., Buckley, R. F., Papp, K. V., Amariglio, R. A., Dewachter, I., Ivanoiu, A., Huijbers, W., Hedden, T., Marshall, G. A., Chhatwal, J. P., Rentz, D. M., Sperling, R. A., & Johnson, K.
Journal titleJAMA Neurology
Page(s)915-924AbstractImportance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials. Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years. Design, Setting, and Participants: Prospective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple Aβ and tau PET observations available on October 31, 2017. Main Outcomes and Measures: A median of 3 Pittsburgh compound B-PET (Aβ, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in Aβ and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment. Results: Of the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high Aβ burden. An antecedent rise in Aβ was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P =.02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P =.001), covarying baseline Aβ and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n = 6) than in those who did not (n = 11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P =.001). A serial mediation model demonstrated that the association between initial Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau. Conclusions and Relevance: We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.
Design and analysis considerations for combining data from multiple biomarker studiesSloan, A., Song, Y., Gail, M. H., Betensky, R., Rosner, B., Ziegler, R. G., Smith-Warner, S. A., & Wang, M.
Journal titleStatistics in Medicine
Page(s)1303-1320AbstractPooling data from multiple studies improves estimation of exposure-disease associations through increased sample size. However, biomarker exposure measurements can vary substantially across laboratories and often require calibration to a reference assay prior to pooling. We develop two statistical methods for aggregating biomarker data from multiple studies: the full calibration method and the internalized method. The full calibration method calibrates all biomarker measurements regardless of the availability of reference laboratory measurements while the internalized method calibrates only non-reference laboratory measurements. We compare the performance of these two aggregation methods to two-stage methods. Furthermore, we compare the aggregated and two-stage methods when estimating the calibration curve from controls only or from a random sample of individuals from the study cohort. Our findings include the following: (1) Under random sampling for calibration, exposure effect estimates from the internalized method have a smaller mean squared error than those from the full calibration method. (2) Under the controls-only calibration design, the full calibration method yields effect estimates with the least bias. (3) The two-stage approaches produce average effect estimates that are similar to the full calibration method under a controls only calibration design and the internalized method under a random sample calibration design. We illustrate the methods in an application evaluating the relationship between circulating vitamin D levels and stroke risk in a pooling project of cohort studies.