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
Concordance measures and time-dependent ROC methodsPantoja-Galicia, N., Okereke, O. I., Blacker, D., & Betensky, R. A.
Journal titleBiostatistics and EpidemiologyAbstractThe 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.
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.
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.
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., Campbell, B. C., 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., Kleinig, T. 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., Yassi, N., 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.
Exploring predictors of response to dacomitinib in EGFR-amplified recurrent glioblastomaChi, A. S., Cahill, D. P., Reardon, D. A., Wen, P. Y., Mikkelsen, T., Peereboom, D. M., Wong, E. T., Gerstner, E. R., Dietrich, J., Plotkin, S. R., Norden, A. D., Lee, E. Q., Nayak, L., Tanaka, S., Wakimoto, H., Lelic, N., Koerner, M. V., Klofas, L. K., Bertalan, M. S., Arrillaga-Romany, I. C., Betensky, R. A., Curry, W. T., Borger, D. R., Balaj, L., Kitchen, R. R., Chakrabortty, S. K., Valentino, M. D., Skog, J., Breakefield, X. O., Iafrate, A. J., & Batchelor, T. T.
Journal titleJCO Precision Oncology
Page(s)593-604AbstractPURPOSE Despite the high frequency of EGFR genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for EGFR gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. PATIENTS AND METHODS We retrospectively explored whether previously described EGFR extracellular domain (ECD)–sensitizing mutations in the context of EGFR gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. RESULTS We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of EGFRvIII or EGFR ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. CONCLUSION While dacomitinib was not effective in most patients with EGFR-amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, EGFRvIII and EGFR ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.
Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanismsLin, Y. F., Smith, A. V., Aspelund, T., Betensky, R. A., Smoller, J. W., Gudnason, V., Launer, L. J., & Blacker, D.
Journal titleAlzheimer's and Dementia
Page(s)65-75AbstractIntroduction: We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition. Methods: For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology. Results: ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification. Discussion: Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E (APOE) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.
New guidelines for statistical reportingBetensky, R. A., & Newberger, N. G. In New England Journal of Medicine.
Nonidentifiability in the presence of factorization for truncated dataVakulenko-Lagun, B., Qian, J., Chiou, S. H., & Betensky, R. A.
Page(s)724-731AbstractA time to event, X , is left-truncated by T if X can be observed only if T < X . This often results in oversampling of large values of X , and necessitates adjustment of estimation procedures to avoid bias. Simple risk-set adjustments can be made to standard risk-set-based estimators to accommodate left truncation when T and X are quasi-independent. We derive a weaker factorization condition for the conditional distribution of T given X in the observable region that permits risk-set adjustment for estimation of the distribution of X , but not of the distribution of T. Quasi-independence results when the analogous factorization condition for X given T holds also, in which case the distributions of X and T are easily estimated. While we can test for factorization, if the test does not reject, we cannot identify which factorization condition holds, or whether quasi-independence holds. Hence we require an unverifiable assumption in order to estimate the distribution of X or T based on truncated data. This contrasts with the common understanding that truncation is different from censoring in requiring no unverifiable assumptions for estimation.We illustrate these concepts through a simulation of left-truncated and right-censored data.
Opposing Roles of apolipoprotein E in aging and neurodegenerationHudry, E., Klickstein, J., Cannavo, C., Jackson, R., Muzikansky, A., Gandhi, S., Urick, D., Argent, T., Wrobleski, L., Roe, A. D., Hou, S. S., Kuchibhotla, K. V., Betensky, R. A., Spires-Jones, T., & Hyman, B. T.
Journal titleLife science alliance
Issue1AbstractApolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer's disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/ PSEN1 mice (8-10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18-20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE's role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.
Serum levels of 25-hydroxyvitamin D at diagnosis are not associated with overall survival in esophageal adenocarcinomaLoehrer, E., Betensky, R. A., Giovannucci, E., Su, L., Shafer, A., Hollis, B. W., & Christiani, D. C.
Journal titleCancer Epidemiology Biomarkers and Prevention
Page(s)1379-1387AbstractBackground: Higher levels of circulating 25-hydroxyvitamin D [25(OH)D] are associated with longer survival in several cancers, but the results have differed across cancer sites. The association between serum 25(OH)D levels and overall survival (OS) time in esophageal adenocarcinoma remains unclear. Methods: We utilized serum samples from 476 patients with primary esophageal adenocarcinoma, recruited from Massachusetts General Hospital (Boston, MA) between 1999 and 2015. We used log-rank tests to test the difference in survival curves across quartiles of 25(OH)D levels and extended Cox modeling to estimate adjusted HRs. We tested for interactions between clinical stage or BMI on the association between 25(OH)D and OS. We additionally performed sensitivity analyses to determine whether race or timing of blood draw (relative to treatment) affected these results. Results: We found no evidence that survival differed across quartiles of 25(OH)D (log rank P = 0.48). Adjusting for confounders, we found no evidence that the hazard of death among the highest quartile of 25(OH)D (quartile 1) differed from any other quartile [quartile 2 HR = 0.90, 95% confidence interval (CI), 0.67-1.23; quartile 3 HR = 1.03, 95% CI, 0.76- 1.38; quartile 4 (lowest) HR = 0.98, 95% CI, 0.72-1.33]. Sensitivity analyses yielded consistent results when accounting for race or time between diagnosis and blood draw. Moreover, we did not find evidence of interaction between 25(OH)D and clinical stage or BMI on OS. Conclusions: Serum level of 25(OH)D near time of diagnosis was not associated with OS in patients with esophageal adenocarcinoma. Impact: Screening 25(OH)D levels among patients with esophageal adenocarcinoma at diagnosis is not clinically relevant to their cancer prognosis based on present evidence.
The impact of amyloid-beta and tau on prospective cognitive decline in older individualsSperling, R. A., Mormino, E. C., Schultz, A. P., Betensky, R. A., Papp, K. V., Amariglio, R. E., Hanseeuw, B. J., Buckley, R., Chhatwal, J., Hedden, T., Marshall, G. A., Quiroz, Y. T., Donovan, N. J., Jackson, J., Gatchel, J. R., Rabin, J. S., Jacobs, H., Yang, H. S., Properzi, M., Kirn, D. R., Rentz, D. M., & Johnson, K. A.
Journal titleAnnals of Neurology
Page(s)181-193AbstractObjectives: Amyloid-beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. Methods: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ ( 11 C-Pittsburgh compound B) and tau ( 18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. Results: Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. Interpretation: Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3 ANN NEUROL 2019;85:181–193.
The missing indicator approach for censored covariates subject to limit of detection in logistic regression modelsChiou, S. H., Betensky, R. A., & Balasubramanian, R.
Journal titleAnnals of Epidemiology
Page(s)57-64AbstractPurpose: In several biomedical studies, one or more exposures of interest may be subject to nonrandom missingness because of the failure of the measurement assay at levels below its limit of detection. This issue is commonly encountered in studies of the metabolome using tandem mass spectrometry–based technologies. Owing to a large number of metabolites measured in these studies, preserving statistical power is of utmost interest. In this article, we evaluate the small sample properties of the missing indicator approach in logistic and conditional logistic regression models. Methods: For nested case-control or matched case control study designs, we evaluate the bias, power, and type I error associated with the missing indicator method using simulation. We compare the missing indicator approach to complete case analysis and several imputation approaches. Results: We show that under a variety of settings, the missing indicator approach outperforms complete case analysis and other imputation approaches with regard to bias, mean squared error, and power. Conclusions: For nested case-control and matched study designs of modest sample sizes, the missing indicator model minimizes loss of information and thus provides an attractive alternative to the oft-used complete case analysis and other imputation approaches.
The p-Value Requires Context, Not a ThresholdBetensky, R. A.
Journal titleAmerican Statistician
Page(s)115-117AbstractIt is widely recognized by statisticians, though not as widely by other researchers, that the p-value cannot be interpreted in isolation, but rather must be considered in the context of certain features of the design and substantive application, such as sample size and meaningful effect size. I consider the setting of the normal mean and highlight the information contained in the p-value in conjunction with the sample size and meaningful effect size. The p-value and sample size jointly yield 95% confidence bounds for the effect of interest, which can be compared to the predetermined meaningful effect size to make inferences about the true effect. I provide simple examples to demonstrate that although the p-value is calculated under the null hypothesis, and thus seemingly may be divorced from the features of the study from which it arises, its interpretation as a measure of evidence requires its contextualization within the study. This implies that any proposal for improved use of the p-value as a measure of the strength of evidence cannot simply be a change to the threshold for significance.
Transformation model estimation of survival under dependent truncation and independent censoringChiou, S. H., Austin, M. D., Qian, J., & Betensky, R. A.
Journal titleStatistical Methods in Medical Research
Page(s)3785-3798AbstractTruncation is a mechanism that permits observation of selected subjects from a source population; subjects are excluded if their event times are not contained within subject-specific intervals. Standard survival analysis methods for estimation of the distribution of the event time require quasi-independence of failure and truncation. When quasi-independence does not hold, alternative estimation procedures are required; currently, there is a copula model approach that makes strong modeling assumptions, and a transformation model approach that does not allow for right censoring. We extend the transformation model approach to accommodate right censoring. We propose a regression diagnostic for assessment of model fit. We evaluate the proposed transformation model in simulations and apply it to the National Alzheimer’s Coordinating Centers autopsy cohort study, and an AIDS incubation study. Our methods are publicly available in an R package, tranSurv.