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
An optimal Wilcoxon–Mann–Whitney test of mortality and a continuous outcomeMatsouaka, R. A., Singhal, A. B., & Betensky, R.
Journal titleStatistical Methods in Medical Research
Page(s)2384-2400We consider a two-group randomized clinical trial, where mortality affects the assessment of a follow-up continuous outcome. Using the worst-rank composite endpoint, we develop a weighted Wilcoxon–Mann–Whitney test statistic to analyze the data. We determine the optimal weights for the Wilcoxon–Mann–Whitney test statistic that maximize its power. We derive a formula for its power and demonstrate its accuracy in simulations. Finally, we apply the method to data from an acute ischemic stroke clinical trial of normobaric oxygen therapy.
Association of anxiety with subcortical amyloidosis in cognitively normal older adultsHanseeuw, B. J., Jonas, V., Jackson, J., Betensky, R., Rentz, D. M., Johnson, K. A., Sperling, R. A., & Donovan, N. J.
Journal titleMolecular PsychiatryLate-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.
Biomarker validation with an imperfect reference: Issues and boundsEmerson, S. C., Waikar, S. S., Fuentes, C., Bonventre, J. V., & Betensky, R.
Journal titleStatistical Methods in Medical Research
Page(s)2933-2945Motivated by the goal of evaluating a biomarker for acute kidney injury, we consider the problem of assessing operating characteristics for a new biomarker when a true gold standard for disease status is unavailable. In this case, the biomarker is typically compared to another imperfect reference test, and this comparison is used to estimate the performance of the new biomarker. However, errors made by the reference test can bias assessment of the new test. Analysis methods like latent class analysis have been proposed to address this issue, generally employing some strong and unverifiable assumptions regarding the relationship between the new biomarker and the reference test. We investigate the conditional independence assumption that is present in many such approaches and show that for a given set of observed data, conditional independence is only possible for a restricted range of disease prevalence values. We explore the information content of the comparison between the new biomarker and the reference test, and give bounds for the true sensitivity and specificity of the new test when operating characteristics for the reference test are known. We demonstrate that in some cases these bounds may be tight enough to provide useful information, but in other cases these bounds may be quite wide.
Correction to: Association of anxiety with subcortical amyloidosis in cognitively normal older adults (Molecular Psychiatry, (2018), 10.1038/s41380-018-0214-2)Hanseeuw, B. J., Jonas, V., Jackson, J., Betensky, R., Rentz, D. M., Johnson, K. A., Sperling, R. A., & Donovan, N. J.
Journal titleMolecular PsychiatryThis Article was originally published under Nature Research’s License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
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 MedicinePooling 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.
Hypothesis Tests for Neyman's Bias in Case–Control StudiesSwanson, D. M., Anderson, C. D., & Betensky, R.
Journal titleJournal of Applied Statistics
Page(s)1956-1977Survival bias is a long recognized problem in case–control studies, and many varieties of bias can come under this umbrella term. We focus on one of them, termed Neyman's bias or ‘prevalence–incidence bias’. It occurs in case–control studies when exposure affects both disease and disease-induced mortality, and we give a formula for the observed, biased odds ratio under such conditions. We compare our result with previous investigations into this phenomenon and consider models under which this bias may or may not be important. Finally, we propose three hypothesis tests to identify when Neyman's bias may be present in case–control studies. We apply these tests to three data sets, one of stroke mortality, another of brain tumors, and the last of atrial fibrillation, and find some evidence of Neyman's bias in the former two cases, but not the last case.
Immunophenotyping of pediatric brain tumors: correlating immune infiltrate with histology, mutational load, and survival and assessing clonal T cell responsePlant, A. S., Koyama, S., Sinai, C., Solomon, I. H., Griffin, G. K., Ligon, K. L., Bandopadhayay, P., Betensky, R., Emerson, R., Dranoff, G., Kieran, M. W., & Ritz, J.
Journal titleJournal of Neuro-Oncology
Page(s)269-278There is little known regarding the immune infiltrate present in pediatric brain tumors and how this compares to what is known about histologically similar adult tumors and its correlation with survival. Here, we provide a descriptive analysis of the immune infiltrate of 22 fresh pediatric brain tumor tissue samples of mixed diagnoses and 40 peripheral blood samples. Samples were analyzed using a flow cytometry panel containing markers for immune cell subtypes, costimulatory markers, inhibitory signals, and markers of activation. This was compared to the standard method of immunohistochemistry (IHC) for immune markers for 89 primary pediatric brain tumors. Both flow cytometry and IHC data did not correlate with the grade of tumor or mutational load and IHC data was not significantly associated with survival for either low grade or high grade gliomas. There is a trend towards a more immunosuppressive phenotype in higher grade tumors with more regulatory T cells present in these tumor types. Both PD1 and PDL1 were present in only a small percentage of the tumor infiltrate. T cell receptor sequencing revealed up to 10% clonality of T cells in tumor infiltrates and no significant difference in clonality between low and high grade gliomas. We have shown the immune infiltrate of pediatric brain tumors does not appear to correlate with grade or survival for a small sample of patients. Further research and larger studies are needed to fully understand the interaction of pediatric brain tumors and the immune system.
Interaction between caffeine and polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2) on Parkinson's disease riskKim, I. Y., O’Reilly, Éilis J., Hughes, K. C., Gao, X., Schwarzschild, M. A., McCullough, M. L., Hannan, M. T., Betensky, R., & Ascherio, A.
Journal titleMovement Disorders
Page(s)414-420Background: Caffeine intake has been inversely associated with Parkinson's disease (PD) risk. This relationship may be modified by polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2), but the results of previous studies have been inconsistent. Method: We examined the interaction of caffeine intake with GRIN2A-rs4998386 and CYP1A2-rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. Matching factors included cohort, birth year, source of DNA, date of DNA collection, and race. Relative risks and 95% confidence intervals were estimated using conditional logistic models. Interactions were tested both on the multiplicative scale and on the additive scale. Results: Overall, caffeine intake was associated with a lower PD risk (adjusted relative risk for highest versus lowest tertile = 0.70; 95% confidence interval, 0.57-0.86; p <.001). In analyses stratified by the GRIN2A-rs4998386 genotype, the multivariable-adjusted relative risk of PD comparing the highest to the lowest tertile of caffeine was 0.69 (95% confidence interval, 0.55-0.88; p <.01) among individuals homozygous for the C allele, and 0.85 (95% confidence interval, 0.55-1.32; p =.47; pRERI =.43) among carriers for the T allele. Interactions between caffeine and GRIN2A were not significant in either the multiplicative or additive scales. We also did not observe significant interactions for CYP1A2-rs762551 and incident PD risk. Conclusion: Our findings do not support the hypothesis of an interaction between the GRIN2A-rs4998386 or CYP1A2-rs762551 polymorphism and caffeine intake in determining PD risk.
Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial resultsFailed generating bibliography.Abstract
Journal titleAnnals of Neurology
Page(s)980-993Objective: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242). Methods: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS). Results: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5–13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0–1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions. Interpretation: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980–993.
Inverse probability weighted Cox regression for doubly truncated dataMandel, M., De Uña-Álvarez, J., Simon, D. K., & Betensky, R.
Page(s)481-487Doubly truncated data arise when event times are observed only if they fall within subject-specific, possibly random, intervals. While non-parametric methods for survivor function estimation using doubly truncated data have been intensively studied, only a few methods for fitting regression models have been suggested, and only for a limited number of covariates. In this article, we present a method to fit the Cox regression model to doubly truncated data with multiple discrete and continuous covariates, and describe how to implement it using existing software. The approach is used to study the association between candidate single nucleotide polymorphisms and age of onset of Parkinson's disease.
Multicrossover Randomized Controlled Trial Designs in Alzheimer DiseaseArnold, S. E., & Betensky, R.
Journal titleAnnals of Neurology
Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brainHopp, S. C., Bihlmeyer, N. A., Corradi, J. P., Vanderburg, C., Cacace, A. M., Das, S., Clark, T. W., Betensky, R., Hyman, B. T., & Hudry, E.
Journal titleJournal of Neurochemistry
Page(s)24-39Synaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid-β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid-β synaptotoxicity. We therefore hypothesized that CN-mediated transcriptional changes may contribute to AD neuropathology and tested this by examining the impact of CN over-expression on neuronal gene expression in vivo. We found dramatic transcriptional down-regulation, especially of synaptic mRNAs, in neurons chronically exposed to CN activation. Importantly, the transcriptional profile parallels the changes in human AD tissue. Bioinformatics analyses suggest that both nuclear factor of activated T cells and numerous microRNAs may all be impacted by CN, and parallel findings are observed in AD. These data and analyses support the hypothesis that at least part of the synaptic failure characterizing AD may result from aberrant CN activation leading to down-regulation of synaptic genes, potentially via activation of specific transcription factors and expression of repressive microRNAs. Open Practices: Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/. (Figure presented.). Read the Editorial Highlight for this article on page 8.
Permutation tests for general dependent truncationFailed generating bibliography.Abstract
Journal titleComputational Statistics and Data Analysis
Page(s)308-324Truncated survival data arise when the event time is observed only if it falls within a subject-specific region, known as the truncation set. Left-truncated data arise when there is delayed entry into a study, such that subjects are included only if their event time exceeds some other time. Quasi-independence of truncation and failure refers to factorization of their joint density in the observable region. Under quasi-independence, standard methods for survival data such as the Kaplan–Meier estimator and Cox regression can be applied after simple adjustments to the risk sets. Unlike the requisite assumption of independent censoring, quasi-independence can be tested, e.g., using a conditional Kendall's tau test. Current methods for testing for quasi-independence are powerful for monotone alternatives. Nonetheless, it is essential to detect any kind of deviation from quasi-independence so as not to report a biased Kaplan–Meier estimator or regression effect, which would arise from applying the simple risk set adjustment when dependence holds. Nonparametric, minimum p-value tests that are powerful against non-monotone alternatives are developed to offer protection against erroneous assumptions of quasi-independence. The use of conditional and unconditional methods of permutation for evaluation of the proposed tests is investigated in simulation studies. The proposed tests are applied to a study on the cognitive and functional decline in aging.
PET staging of amyloidosis using striatumFailed generating bibliography.Abstract
Journal titleAlzheimer's and Dementia
Page(s)1281-1292Introduction: Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures. Methods: We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition. Results: Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid. Discussion: PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research.
Polygenic pleiotropy and potential causal relationships between educational attainment, neurobiological profile, and positive psychotic symptomsLin, Y. F., Chen, C. Y., Öngür, D., Betensky, R., Smoller, J. W., Blacker, D., & Hall, M. H.
Journal titleTranslational Psychiatry
Issue1Event-related potential (ERP) components have been used to assess cognitive functions in patients with psychotic illness. Evidence suggests that among patients with psychosis there is a distinct heritable neurophysiologic phenotypic subtype captured by impairments across a range of ERP measures. In this study, we investigated the genetic basis of this "globally impaired" ERP cluster and its relationship to psychosis and cognitive abilities. We applied K-means clustering to six ERP measures to re-derive the globally impaired (n = 60) and the non-globally impaired ERP clusters (n = 323) in a sample of cases with schizophrenia (SCZ = 136) or bipolar disorder (BPD = 121) and healthy controls (n = 126). We used genome-wide association study (GWAS) results for SCZ, BPD, college completion, and childhood intelligence as the discovery datasets to derive polygenic risk scores (PRS) in our study sample and tested their associations with globally impaired ERP. We conducted mediation analyses to estimate the proportion of each PRS effect on severity of psychotic symptoms that is mediated through membership in the globally impaired ERP. Individuals with globally impaired ERP had significantly higher PANSS-positive scores (β = 3.95, P = 0.005). The SCZ-PRS was nominally associated with globally impaired ERP (unadjusted P = 0.01; R 2 = 3.07%). We also found a significant positive association between the college-PRS and globally impaired ERP (FDR-corrected P = 0.004; R 2 = 6.15%). The effect of college-PRS on PANSS positivity was almost entirely (97.1%) mediated through globally impaired ERP. These results suggest that the globally impaired ERP phenotype may represent some aspects of brain physiology on the path between genetic influences on educational attainment and psychotic symptoms.
Probing tumor microenvironment in patients with newly diagnosed glioblastoma during chemoradiation and adjuvant temozolomide with functional MRIIna Ly, K., Vakulenko-Lagun, B., Emblem, K. E., Ou, Y., Da, X., Betensky, R., Kalpathy-Cramer, J., Duda, D. G., Jain, R. K., Chi, A. S., Plotkin, S. R., Batchelor, T. T., Sorensen, G., Rosen, B. R., & Gerstner, E. R.
Journal titleScientific reports
Issue1Functional MRI may identify critical windows of opportunity for drug delivery and distinguish between early treatment responders and non-responders. Using diffusion-weighted, dynamic contrast-enhanced, and dynamic susceptibility contrast MRI, as well as pro-angiogenic and pro-inflammatory blood markers, we prospectively studied the physiologic tumor-related changes in fourteen newly diagnosed glioblastoma patients during standard therapy. 153 MRI scans and blood collection were performed before chemoradiation (baseline), weekly during chemoradiation (week 1–6), monthly before each cycle of adjuvant temozolomide (pre-C1-C6), and after cycle 6. The apparent diffusion coefficient, volume transfer coefficient (Ktrans), and relative cerebral blood volume (rCBV) and flow (rCBF) were calculated within the tumor and edema regions and compared to baseline. Cox regression analysis was used to assess the effect of clinical variables, imaging, and blood markers on progression-free (PFS) and overall survival (OS). After controlling for additional covariates, high baseline rCBV and rCBF within the edema region were associated with worse PFS (microvessel rCBF: HR = 7.849, p = 0.044; panvessel rCBV: HR = 3.763, p = 0.032; panvessel rCBF: HR = 3.984; p = 0.049). The same applied to high week 5 and pre-C1 Ktrans within the tumor region (week 5 Ktrans: HR = 1.038, p = 0.003; pre-C1 Ktrans: HR = 1.029, p = 0.004). Elevated week 6 VEGF levels were associated with worse OS (HR = 1.034; p = 0.004). Our findings suggest a role for rCBV and rCBF at baseline and Ktrans and VEGF levels during treatment as markers of response. Functional imaging changes can differ substantially between tumor and edema regions, highlighting the variable biologic and vascular state of tumor microenvironment during therapy.
rBPI21 (opebacan) promotes rapid trilineage hematopoietic recovery in a murine model of high-dose total body irradiationJanec, K. J., Yuan, H., Norton, J. E., Kelner, R. H., Hirt, C. K., Betensky, R., & Guinan, E. C.
Journal titleAmerican Journal of Hematology
Page(s)1002-1013The complexity of providing adequate care after radiation exposure has drawn increasing attention. While most therapeutic development has focused on improving survival at lethal radiation doses, acute hematopoietic syndrome (AHS) occurs at substantially lower exposures. Thus, it is likely that a large proportion of such a radiation-exposed population will manifest AHS of variable degree and that the medical and socioeconomic costs of AHS will accrue. Here, we examined the potential of rBPI21 (opebacan), used without supportive care, to accelerate hematopoietic recovery after radiation where expected survival was substantial (42%-75%) at 30 days. rBPI21 administration was associated with accelerated recovery of hematopoietic precursors and normal marrow cellularity, with increases in megakaryocyte numbers particularly marked. This translated into attaining normal trilineage peripheral blood counts 2-3 weeks earlier than controls. Elevations of hematopoietic growth factors observed in plasma and the marrow microenvironment suggest the mechanism is likely multifactorial and not confined to known endotoxin-neutralizing and cytokine downmodulating activities of rBPI21. These observations deserve further exploration in radiation models and other settings where inadequate hematopoiesis is a prominent feature. These experiments also model the potential of therapeutics to limit the allocation of scarce resources after catastrophic exposures as an endpoint independent of lethality mitigation.
Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's diseaseBennett, R. E., Robbins, A. B., Hu, M., Cao, X., Betensky, R., Clark, T., Das, S., & Hyman, B. T.
Journal titleProceedings of the National Academy of Sciences of the United States of America
Page(s)E1289-E1298Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.
The prognostic value of histopathologic lesions in native kidney biopsy specimens: Results from the Boston kidney biopsy cohort studySrivastava, A., Palsson, R., Kaze, A. D., Chen, M. E., Palacios, P., Sabbisetti, V., Betensky, R., Steinman, T. I., Thadhani, R. I., McMahon, G. M., Stillman, I. E., Rennke, H. G., & Waikar, S. S.
Journal titleJournal of the American Society of Nephrology
Page(s)2213-2224Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data. Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression ($40% eGFR decline or RRT). Results Mean baseline eGFR was 57.5636.0 ml/min per 1.73 m2. During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27). Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.
Time-to-event data with time-varying biomarkers measured only at study entry, with applications to Alzheimer's diseaseFailed generating bibliography.Abstract
Journal titleStatistics in Medicine
Page(s)914-932Relating time-varying biomarkers of Alzheimer's disease to time-to-event using a Cox model is complicated by the fact that Alzheimer's disease biomarkers are sparsely collected, typically only at study entry; this is problematic since Cox regression with time-varying covariates requires observation of the covariate process at all failure times. The analysis might be simplified by using study entry as the time origin and treating the time-varying covariate measured at study entry as a fixed baseline covariate. In this paper, we first derive conditions under which using an incorrect time origin of study entry results in consistent estimation of regression parameters when the time-varying covariate is continuous and fully observed. We then derive conditions under which treating the time-varying covariate as fixed at study entry results in consistent estimation. We provide methods for estimating the regression parameter when a functional form can be assumed for the time-varying biomarker, which is measured only at study entry. We demonstrate our analytical results in a simulation study and apply our methods to data from the Rush Religious Orders Study and Memory and Aging Project and data from the Alzheimer's Disease Neuroimaging Initiative.
Wide Range of Clinical Outcomes in Patients with Gliomatosis Cerebri Growth Pattern: A Clinical, Radiographic, and Histopathologic StudyLy, K. I., Oakley, D. H., Pine, A. B., Frosch, M. P., Chiou, S. H., Betensky, R., Pomerantz, S. R., Hochberg, F. H., Batchelor, T. T., Cahill, D. P., & Dietrich, J.
Journal titleOncologistBackground: The 2016 World Health Organization Classification of Central Nervous System Tumors categorizes gliomatosis cerebri growth pattern (GC) as a subgroup of diffuse infiltrating gliomas, defined by extent of brain involvement on magnetic resonance imaging (MRI). Clinical and radiographic features in GC patients are highly heterogeneous; however, prognosis has historically been considered poor. Subjects, Materials, and Methods: We performed a retrospective search for patients at our institution meeting radiographic criteria of primary, type I GC (defined as diffuse tumor infiltration without associated tumor mass and contrast enhancement on MRI) and analyzed their clinical, imaging, and histopathologic features. Results: A total of 34 patients met radiographic criteria of primary, type I GC, and 33 had a confirmed histologic diagnosis of an infiltrating glial neoplasm. Age >47 years at diagnosis was associated with worse overall survival (OS) compared with age ≤47 years (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01–1.07, p =.003). Patients with grade 2 tumors demonstrated a trend for improved OS compared with those with grade 3 tumors (HR 2.65, 95% CI 0.99–7.08, p =.051). Except for brainstem involvement, extent or location of radiographic involvement did not detectably affect clinical outcome. IDH mutation status identified a subgroup of GC patients with particularly long survival up to 25 years and was associated with longer time to progression (HR 4.81, 95% CI 0.99–23.47, p =.052). Conclusion: Patients with primary, type I GC do not uniformly carry a poor prognosis, even in the presence of widespread radiographic involvement. Consistent with other reports, IDH mutation status may identify patients with improved clinical outcome. Molecular characterization, rather than MRI features, may be most valuable for prognostication and management of GC patients. Implications for Practice: Patients with gliomatosis cerebri growth pattern (GC) constitute a challenge to clinicians, given their wide range of clinical, histologic, and radiographic presentation, heterogeneous outcome patterns, and the lack of consensus on a standardized treatment approach. This study highlights that radiographic extent of disease—albeit category-defining—does not detectably influence survival and that IDH mutations may impact clinical outcome. Practicing oncologists should be aware that select GC patients may demonstrate exceptionally favorable survival times and prognosticate patients based on molecular markers, rather than imaging features alone.
APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohortsQian, J., Wolters, F. J., Beiser, A., Haan, M., Ikram, M. A., Karlawish, J., Langbaum, J. B., Neuhaus, J. M., Reiman, E. M., Roberts, J. S., Seshadri, S., Tariot, P. N., Woods, B. M., Betensky, R., & Blacker, D.
Journal titlePLoS Medicine
Issue3Background: With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer’s Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals. Methods and findings: We included cognitively unimpaired individuals aged 60–75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer’s Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60–64, 65–69, 70–75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60–64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65–69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70–75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80–85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%–38.45% at age 60–64 y, 30.76%–40.26% at 65–69 y, and 33.3%–35.17% at 70–75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables. Conclusions: Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies—with implications for informed consent and design for clinical trials targeting high-risk individuals.
Association of cancer and Alzheimer's disease risk in a national cohort of veteransFrain, L., Swanson, D., Cho, K., Gagnon, D., Lu, K. P., Betensky, R., & Driver, J.
Journal titleAlzheimer's and Dementia
Page(s)1364-1370Introduction: To examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. Methods: Retrospective cohort of 3,499,378 mostly male US veterans aged ≥65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. Results: Survivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. Discussion: Survivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD.
Bayesian Variable Selection Methods for Matched Case-Control StudiesAsafu-Adjei, J., Mahlet, G. T., Coull, B., Balasubramanian, R., Lev, M., Schwamm, L., & Betensky, R.
Journal titleInternational Journal of Biostatistics
Issue1Matched case-control designs are currently used in many biomedical applications. To ensure high efficiency and statistical power in identifying features that best discriminate cases from controls, it is important to account for the use of matched designs. However, in the setting of high dimensional data, few variable selection methods account for matching. Bayesian approaches to variable selection have several advantages, including the fact that such approaches visit a wider range of model subsets. In this paper, we propose a variable selection method to account for case-control matching in a Bayesian context and apply it using simulation studies, a matched brain imaging study conducted at Massachusetts General Hospital, and a matched cardiovascular biomarker study conducted by the High Risk Plaque Initiative.
Cognitive resilience in clinical and preclinical Alzheimer’s disease: the Association of Amyloid and Tau Burden on cognitive performanceRentz, D. M., Mormino, E. C., Papp, K. V., Betensky, R., Sperling, R. A., & Johnson, K. A.
Journal titleBrain Imaging and Behavior
Page(s)383-390We explored the cross-sectional relationships between β-amyloid (Aβ) and inferior temporal tau deposition (IFT Tau) on cognitive performance and whether cognitive reserve (CR) modifies these associations. We studied 156 participants classified into groups of clinically normal (CN = 133), mild cognitive impairment (MCI = 17) and Alzheimer disease (AD = 6) dementia. AMNART IQ served as a proxy of CR and cognitive performance was assessed using the MMSE. In separate linear regression models predicting MMSE, we examined the interactions of CR x global Aβ and CR x IFT tau across all participants and within the CN group alone. In the whole sample, the interaction between CR and IFT tau was significant (p < 0.003), such that higher CR participants with elevated IFT tau had better MMSE scores compared with low CR participants with similar levels of IFT tau. The interaction between CR and Aβ status did not reach significance (p = 0.093). In CN only, no cross-sectional interactions among CR, Aβ, and IFT tau were observed on MMSE. These findings imply that CR may be protective against early AD processes and enable some individuals to remain cognitively stable despite elevated tau and Aβ burden.