Ravi Varadhan | Johns Hopkins University (original) (raw)
Papers by Ravi Varadhan
Innovation in Aging, 2020
Bone marrow transplant (BMT) is a curative therapy for patients with hematologic malignancies. Ho... more Bone marrow transplant (BMT) is a curative therapy for patients with hematologic malignancies. However, there is still a high rate of relapse and mortality after BMT. It would be tremendously valuable if we can identify older adults at high-risk for mortality using readily available information. A number of biomarkers are routinely collected during follow-up for clinical care, but this information is seldom used in prediction models. We examined the data from 1011 patients who had BMT at Johns Hopkins between 2013 and 2019. There were 364 death over a median follow-up of 431 days. We considered 4 biomarkers: albumin, hemoglobin, lymphocytes count, and platelets. Biomarker data from one week pre-BMT to 8 weeks post-BMT was used for prediction using a random survival forest model. The model performed quite well and had a 5-fold cross-validated c-index of 0.733 (95%CI: 0.724-0.739). Routine laboratory biomarkers can help identify poorly resilient older BMT patients.
Leukemia & Lymphoma
There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative over... more There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative overlap neoplasm (MPN) patients' response to hypomethylating agents (HMA). Forty-three patients with MDS/MPN who were treated with HMA during chronic phase and had next-generation sequencing using the established 63-genes panel were identified. Complete and partial remission and marrow response were assessed based on the MDS/MPN International Working Group response criteria. On univariate analysis, younger age, higher number of mutations, and mutations in SETBP1, RUNX1, or EZH2 were associated with no response. Multivariable analysis for modeling response were conducted via least absolute shrinkage and selection operator logistic regression approach, and showed that mutations in SETBP1, RUNX1, or EZH2 predict lack of HMA response. While limited by sample size, our findings suggest that genomic landscape can potentially identify MDS/MPN patients with lower likelihood of response to HMA.
Blood, 2021
INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MD... more INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN) remains challenging due to their molecular complexity. Hypo-methylating agents (HMA) have been used for cytoreduction and preparation of patients for allogeneic blood or marrow transplantation (BMT). However, less than 50% patients have a meaningful response to HMA and predictive factors for response remain unknown. The aim of our study is to examine molecular predictors of response to HMA in patients with MDS/MPN. PATIENTS AND METHODS: We performed a retrospective analysis of 150 patients evaluated at our center for chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MDS/MPN-U) between 1/1/2010 and 12/31/2020. Forty-three individuals who were treated with HMA during chronic phase and had next generation sequencing (NGS) using the established 63-genes panel were identified. Complete and partial remission (CR and PR), and mar...
arXiv: Methodology, 2020
Shrinkage estimates of small domain parameters typically utilize a combination of a noisy "d... more Shrinkage estimates of small domain parameters typically utilize a combination of a noisy "direct" estimate that only uses data from a specific small domain and a more stable regression estimate. When the regression model is misspecified, estimation performance for the noisier domains can suffer due to substantial shrinkage towards a poorly estimated regression surface. In this paper, we introduce a new class of robust, empirically-driven regression weights that target estimation of the small domain means under potential misspecification of the global regression model. Our regression weights are a convex combination of the model-based weights associated with the best linear unbiased predictor (BLUP) and those associated with the observed best predictor (OBP). The compromise parameter in this convex combination is found by minimizing a novel, unbiased estimate of the mean-squared prediction error for the small domain means, and we label the associated small domain estimates...
The information in this report is intended to help health care decisionmakers-patients and clinic... more The information in this report is intended to help health care decisionmakers-patients and clinicians, health system leaders, and policymakers, among others-make well informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This document was written with support from the Effective Health Care Program at AHRQ. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted, for which further reproduction is prohibited without the specific permission of copyright holders. The investigators have no relevant financial interests in the report. The investigators have no employment, consultancies, honoraria, or stock ownership or options, or royalties from any organization or entity with a financial interest or financial conflict with the subject matter discussed in the report.
Description Provides a replacement and extension of the optim() function to unify and streamline ... more Description Provides a replacement and extension of the optim() function to unify and streamline optimization capabilities in R for smooth, possibly box constrained functions of several or many parameters. This is the CRAN version of the package.
Title A Suite of Convergence Acceleration Schemes for EM and MM algorithms Description Algorithms... more Title A Suite of Convergence Acceleration Schemes for EM and MM algorithms Description Algorithms for accelerating the convergence of slow,monotone sequences from smooth, contraction mapping such as the EM and MM algorithms. It can be used to accelerate any smooth,linearly convergent acceleration scheme. A tutorial style introduction to this package is available in a vignette on the CRAN download page or, when the package is loaded in an R session, with vignette(‘‘turboEM’’). Depends R (> = 2.12.0), numDeriv, methods, graphics, quantreg, foreach
Description This package estimates parameters of a Gaussian copula,treating the univariate margin... more Description This package estimates parameters of a Gaussian copula,treating the univariate marginal distributions as nuisance parameters as described in Hoff(2007). It also provides a semiparametric imputation procedure for missing multivariate data. License GPL (> = 2)
Description Derivative-Free optimization algorithms. These algorithms do not require gradient inf... more Description Derivative-Free optimization algorithms. These algorithms do not require gradient information. More importantly, they can be used to solve non-smooth optimization problems.
This document gives a brief introduction to the main functions of the anoint package. The package... more This document gives a brief introduction to the main functions of the anoint package. The package provides a set of tools for the “analysis of interactions” to investigate consistency of treatment effect with data from a parallel-group clinical trial. The examples will make use of a simulated clinical trial data set, motivated by the structure of the Studies of Left Ventricular Dysfunction Trial (SOLVD-T), a placebo-controlled trial of the angiotensin-converting-enzyme inhibitor enalapril for patients with congestive heart failure (Yusuf 1991). The simulated data set is included with the package.
The Journals of Gerontology: Series A, 2021
Background Total knee replacement (TKR) is a common procedure in older adults. Physical resilienc... more Background Total knee replacement (TKR) is a common procedure in older adults. Physical resilience may be a useful construct to explain variable outcomes. We sought to define a simple measure of physical resilience and identify risk factors for nonresilient patient outcomes. Methods Secondary analysis of Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) cohort study, a prospective registry of total joint replacement. The analysis included 7 239 adults aged 60 or older who underwent TKR between 2011 and 2015. Measures included sociodemographic and health factors. Outcomes were categorized as physically resilient versus nonresilient based on the change from baseline to 1-year follow-up for 3 patient-reported outcomes: the physical component summary (PCS), bodily pain (BP), and vitality (VT) from the Short Form-36 subcomponent scores, at preop and 1-year postprocedure. Associations were expressed as relative risk (RR) of physically nonr...
Journal of Clinical Oncology, 2020
7544 Background: LGL - often called LGL leukemia - is a clonal disorder of T or NK cells often as... more 7544 Background: LGL - often called LGL leukemia - is a clonal disorder of T or NK cells often associated with cytopenias, autoimmunity, splenomegaly, and B symptoms. There are a limited number of studies of benign LGL expansion after alloBMT, some suggesting an association with improved transplant-related outcomes. In contrast, clinically significant LGL leukemia after alloBMT is only described in case reports. Methods: We cross referenced all patients receiving an alloBMT at Johns Hopkins since 2010 with patients who were evaluated for LGL expansion by peripheral blood (PB) flow cytometry (FC) since 2012. Results: There were 1930 alloBMTs from 1/1/10 to 7/1/19. PB FC for suspected LGL was sent on 153 unique patients after alloBMT, usually in the setting of cytopenias (97%). Median age was 59. 69 (45%) had LGL expansion (LGL+) at a median 194 days after alloBMT. Among LGL+, 53 (77%) had an absolute neutrophil count (ANC) < 1500. The majority of the alloBMTs were non-myeloablativ...
Journal of Clinical Epidemiology, 2018
When baseline risk of an outcome varies within a population, the effect of a treatment on that ou... more When baseline risk of an outcome varies within a population, the effect of a treatment on that outcome will vary on at least one scale (e.g., additive, multiplicative). This treatment effect heterogeneity is of interest in patient-centered outcomes research. Based on a literature review and solicited expert opinion, we assert: 1) Treatment effect heterogeneity on the additive scale is most interpretable to healthcare providers and patients using effect estimates to guide treatment decision making; heterogeneity reported on the multiplicative scale may be misleading as to the magnitude or direction of a substantively important interaction. 2) The additive scale may give clues about sufficient-cause interaction, although such interaction is typically not relevant to patients' treatment choices. 3) Statistical modeling need not be conducted on the same scale as results are communicated. 4) Statistical testing is one tool for investigations, provided important subgroups are identified a priori, but test results should be interpreted cautiously given non-equivalence of statistical and clinical significance. 5) Qualitative interactions should be evaluated in a prespecified manner for important subgroups. Principled analytic plans that take into account the purpose of investigation of treatment effect heterogeneity are likely to yield more useful results for guiding treatment decisions.
Medical care, Jul 21, 2017
Fried and colleagues described a frailty phenotype measured in the Cardiovascular Health Study (C... more Fried and colleagues described a frailty phenotype measured in the Cardiovascular Health Study (CHS). This phenotype is manifest when ≥3 of the following are present: low grip strength, low energy, slowed waking speed, low physical activity, or unintentional weight loss. We sought to approximate frailty phenotype using only administrative claims data to enable frailty to be assessed without physical performance measures. We used the CHS cohort data linked to participants Medicare claims. The reference standard was the frailty phenotype measured at visits 5 and 9. With penalized logistic regression, we developed a parsimonious index for predicting the frailty phenotype using a linear combination of diagnoses, operationalized with claims data. We assessed the predictive validity of frailty index by examining how well it predicted common aging-related outcomes including hospitalization, disability, and death. There were 4454 CHS participants from 4 clinical sites. In total, 84% were wh...
American Journal of Epidemiology, 2016
Different phenotypes have increasingly been used as tools for clinical characterization of frailt... more Different phenotypes have increasingly been used as tools for clinical characterization of frailty among older adults. Although there have been studies about the comparability and effectiveness of various simplifications and approximations of existing frailty phenotypes for risk prediction, there have been no studies in which investigators evaluated the stability of the clinical characterization achieved. In the present study, we used baseline (1992-1996) data from 786 community-dwelling women who were 70-79 years of age in the Women's Health and Aging Study I and II to compare physical frailty phenotypes (PFPs). Using the 5 criteria set forth by Fried, we created 15 PFPs that were positive for various combinations of 3 or 4 of those criteria and compared them with the PFP that included all 5 criteria in order to assess construct validity with regard to frailty syndrome characterization and predictive validity for adverse outcomes of aging. All PFPs exhibited high specificity and negative predictive values for identifying frailty syndrome. Three-item PFPs were insensitive but were the best performers for positive predictive value, with the highest positive predictive value of 0.86 seen in the PFP characterized by the combination of weakness, exhaustion, and weight loss. In comparison, the 5-criterion PFP achieved a sensitivity of 0.82 but a positive predictive value of only 0.53. With regard to predictive validity, it was not merely the number of criteria used to characterize the PFPs but rather the specific criteria combinations that predicted the risk of adverse outcomes. Our findings show that there clinically important contexts in which simplified PFPs cannot be used interchangeably.
Journal of Statistical Software, 2009
We discuss R package BB, in particular, its capabilities for solving a nonlinear system of equati... more We discuss R package BB, in particular, its capabilities for solving a nonlinear system of equations. The function BBsolve in BB can be used for this purpose. We demonstrate the utility of these functions for solving: (a) large systems of nonlinear equations, (b) smooth, nonlinear estimating equations in statistical modeling, and (c) non-smooth estimating equations arising in rank-based regression modeling of censored failure time data. The function BBoptim can be used to solve smooth, box-constrained optimization problems. A main strength of BB is that, due to its low memory and storage requirements, it is ideally suited for solving high-dimensional problems with thousands of variables.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009
Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased com... more Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased complexity in their output. For example, the degradation of cardiac autonomic control results in loss of complexity in the heart rate signal. Frailty is a state of critically impaired homeostasis that results in heightened vulnerability to stressors. We propose a new measure of heart rate variability (HRV) to capture the impairment in cardiac autonomic control associated with frailty. Methods. Traditional time and frequency domain indices of HRV were obtained from 2-hour ambulatory electrocardiograms (ECGs) of 276 women (65-101 years old) in the Women ' s Health and Aging Study-I. Principal components analysis was conducted on the correlation matrix of HRV indices. Frailty was defi ned using a validated instrument. Regression models were used to evaluate associations of HRV measures with age, frailty, and 5-year mortality. Results. The fi rst two principal components (PCs), PC1 and PC2, explained 90% of the variance in HRV indices. PC1 is the mean of log-transformed HRV indices. PC2 is a linear combination of log-transformed indices, with positive weights for very low frequency (VLF), low frequency (LF), and standard deviation of N-N intervals (SDNN), and negative weights for high frequency (HF), root-mean-squared differences of successive N-N intervals (RMSSD), and proportion of all N-N intervals that are larger than 50 ms (pNN50). Decreases in SDNN, VLF, LF, and LF/HF were associated with an increased risk of frailty. PC2 was more strongly associated with age (b = − .23, p < .001) and frailty (b = − .73, p < 10 − 5) than were the individual HRV indices and LF/HF. PC2 was also the best predictor of 5-year mortality (b = − .60, p < 10 − 6). Conclusions. Cardiac autonomic control, as refl ected by HRV, is impaired in frailty. A new measure derived from PC aggregation of traditional HRV indices provides a compact summary of this impairment.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009
I t has been proposed that frailty, a syndrome of old age, results from an impairment across phys... more I t has been proposed that frailty, a syndrome of old age, results from an impairment across physiological systems (1) that leads to loss of homeostatic resilience. the hallmarks of this loss of integration of physiological function are increased susceptibility to stressors and even death. Because homeostatic resilience is inherently dynamic, losses are more likely to be unmasked as impaired ability to respond to a stressor than as a change in function under resting conditions. Frailty is thought to manifest a loss of physiological complexity as a qualitative change in the manner, not just a diminished amount, of response to stress via several physiological systems (2). However, this theory remains to be evaluated. Few frail older adults have been tested through stress tests, so the loss of function that would be evident from studying interactions among physiological systems under stress remains largely theoretical (3). A clinical phenotypic or operational definition of physical frailty composed of several components among weakness, slowness, low activity, exhaustion, and weight loss has been shown to have construct and predictive validity as evi-denced by its association with increased risk of future physical disability and death (4) and discriminant validity as a syndrome (5). Although frailty is thought to result from functional decline in several systems, including immunologic, hormonal, and neural (6,7), a central feature embedded in the frailty criteria is lower extremity exercise capacity (EC). We hypothesized that the systems involved in converting energy into lower extremity EC interact, that is, respond differently to each other in frail adults compared with non-frail adults. Identifying a difference in integrated function according to frailty status would contribute in previously unexplained ways to our current understanding of EC in late life. this study aimed to address these questions by: (a) determining the relationship between key physiological systems and EC in disabled older women, a cohort that provides an opportunity to study frailty but is underrepresented in physiology literature and (b) evaluating for interactions among these systems with frailty status with respect to their association with lower extremity EC obtained through a graded
Innovation in Aging, 2020
Bone marrow transplant (BMT) is a curative therapy for patients with hematologic malignancies. Ho... more Bone marrow transplant (BMT) is a curative therapy for patients with hematologic malignancies. However, there is still a high rate of relapse and mortality after BMT. It would be tremendously valuable if we can identify older adults at high-risk for mortality using readily available information. A number of biomarkers are routinely collected during follow-up for clinical care, but this information is seldom used in prediction models. We examined the data from 1011 patients who had BMT at Johns Hopkins between 2013 and 2019. There were 364 death over a median follow-up of 431 days. We considered 4 biomarkers: albumin, hemoglobin, lymphocytes count, and platelets. Biomarker data from one week pre-BMT to 8 weeks post-BMT was used for prediction using a random survival forest model. The model performed quite well and had a 5-fold cross-validated c-index of 0.733 (95%CI: 0.724-0.739). Routine laboratory biomarkers can help identify poorly resilient older BMT patients.
Leukemia & Lymphoma
There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative over... more There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative overlap neoplasm (MPN) patients' response to hypomethylating agents (HMA). Forty-three patients with MDS/MPN who were treated with HMA during chronic phase and had next-generation sequencing using the established 63-genes panel were identified. Complete and partial remission and marrow response were assessed based on the MDS/MPN International Working Group response criteria. On univariate analysis, younger age, higher number of mutations, and mutations in SETBP1, RUNX1, or EZH2 were associated with no response. Multivariable analysis for modeling response were conducted via least absolute shrinkage and selection operator logistic regression approach, and showed that mutations in SETBP1, RUNX1, or EZH2 predict lack of HMA response. While limited by sample size, our findings suggest that genomic landscape can potentially identify MDS/MPN patients with lower likelihood of response to HMA.
Blood, 2021
INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MD... more INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN) remains challenging due to their molecular complexity. Hypo-methylating agents (HMA) have been used for cytoreduction and preparation of patients for allogeneic blood or marrow transplantation (BMT). However, less than 50% patients have a meaningful response to HMA and predictive factors for response remain unknown. The aim of our study is to examine molecular predictors of response to HMA in patients with MDS/MPN. PATIENTS AND METHODS: We performed a retrospective analysis of 150 patients evaluated at our center for chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MDS/MPN-U) between 1/1/2010 and 12/31/2020. Forty-three individuals who were treated with HMA during chronic phase and had next generation sequencing (NGS) using the established 63-genes panel were identified. Complete and partial remission (CR and PR), and mar...
arXiv: Methodology, 2020
Shrinkage estimates of small domain parameters typically utilize a combination of a noisy "d... more Shrinkage estimates of small domain parameters typically utilize a combination of a noisy "direct" estimate that only uses data from a specific small domain and a more stable regression estimate. When the regression model is misspecified, estimation performance for the noisier domains can suffer due to substantial shrinkage towards a poorly estimated regression surface. In this paper, we introduce a new class of robust, empirically-driven regression weights that target estimation of the small domain means under potential misspecification of the global regression model. Our regression weights are a convex combination of the model-based weights associated with the best linear unbiased predictor (BLUP) and those associated with the observed best predictor (OBP). The compromise parameter in this convex combination is found by minimizing a novel, unbiased estimate of the mean-squared prediction error for the small domain means, and we label the associated small domain estimates...
The information in this report is intended to help health care decisionmakers-patients and clinic... more The information in this report is intended to help health care decisionmakers-patients and clinicians, health system leaders, and policymakers, among others-make well informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This document was written with support from the Effective Health Care Program at AHRQ. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted, for which further reproduction is prohibited without the specific permission of copyright holders. The investigators have no relevant financial interests in the report. The investigators have no employment, consultancies, honoraria, or stock ownership or options, or royalties from any organization or entity with a financial interest or financial conflict with the subject matter discussed in the report.
Description Provides a replacement and extension of the optim() function to unify and streamline ... more Description Provides a replacement and extension of the optim() function to unify and streamline optimization capabilities in R for smooth, possibly box constrained functions of several or many parameters. This is the CRAN version of the package.
Title A Suite of Convergence Acceleration Schemes for EM and MM algorithms Description Algorithms... more Title A Suite of Convergence Acceleration Schemes for EM and MM algorithms Description Algorithms for accelerating the convergence of slow,monotone sequences from smooth, contraction mapping such as the EM and MM algorithms. It can be used to accelerate any smooth,linearly convergent acceleration scheme. A tutorial style introduction to this package is available in a vignette on the CRAN download page or, when the package is loaded in an R session, with vignette(‘‘turboEM’’). Depends R (> = 2.12.0), numDeriv, methods, graphics, quantreg, foreach
Description This package estimates parameters of a Gaussian copula,treating the univariate margin... more Description This package estimates parameters of a Gaussian copula,treating the univariate marginal distributions as nuisance parameters as described in Hoff(2007). It also provides a semiparametric imputation procedure for missing multivariate data. License GPL (> = 2)
Description Derivative-Free optimization algorithms. These algorithms do not require gradient inf... more Description Derivative-Free optimization algorithms. These algorithms do not require gradient information. More importantly, they can be used to solve non-smooth optimization problems.
This document gives a brief introduction to the main functions of the anoint package. The package... more This document gives a brief introduction to the main functions of the anoint package. The package provides a set of tools for the “analysis of interactions” to investigate consistency of treatment effect with data from a parallel-group clinical trial. The examples will make use of a simulated clinical trial data set, motivated by the structure of the Studies of Left Ventricular Dysfunction Trial (SOLVD-T), a placebo-controlled trial of the angiotensin-converting-enzyme inhibitor enalapril for patients with congestive heart failure (Yusuf 1991). The simulated data set is included with the package.
The Journals of Gerontology: Series A, 2021
Background Total knee replacement (TKR) is a common procedure in older adults. Physical resilienc... more Background Total knee replacement (TKR) is a common procedure in older adults. Physical resilience may be a useful construct to explain variable outcomes. We sought to define a simple measure of physical resilience and identify risk factors for nonresilient patient outcomes. Methods Secondary analysis of Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement (FORCE-TJR) cohort study, a prospective registry of total joint replacement. The analysis included 7 239 adults aged 60 or older who underwent TKR between 2011 and 2015. Measures included sociodemographic and health factors. Outcomes were categorized as physically resilient versus nonresilient based on the change from baseline to 1-year follow-up for 3 patient-reported outcomes: the physical component summary (PCS), bodily pain (BP), and vitality (VT) from the Short Form-36 subcomponent scores, at preop and 1-year postprocedure. Associations were expressed as relative risk (RR) of physically nonr...
Journal of Clinical Oncology, 2020
7544 Background: LGL - often called LGL leukemia - is a clonal disorder of T or NK cells often as... more 7544 Background: LGL - often called LGL leukemia - is a clonal disorder of T or NK cells often associated with cytopenias, autoimmunity, splenomegaly, and B symptoms. There are a limited number of studies of benign LGL expansion after alloBMT, some suggesting an association with improved transplant-related outcomes. In contrast, clinically significant LGL leukemia after alloBMT is only described in case reports. Methods: We cross referenced all patients receiving an alloBMT at Johns Hopkins since 2010 with patients who were evaluated for LGL expansion by peripheral blood (PB) flow cytometry (FC) since 2012. Results: There were 1930 alloBMTs from 1/1/10 to 7/1/19. PB FC for suspected LGL was sent on 153 unique patients after alloBMT, usually in the setting of cytopenias (97%). Median age was 59. 69 (45%) had LGL expansion (LGL+) at a median 194 days after alloBMT. Among LGL+, 53 (77%) had an absolute neutrophil count (ANC) < 1500. The majority of the alloBMTs were non-myeloablativ...
Journal of Clinical Epidemiology, 2018
When baseline risk of an outcome varies within a population, the effect of a treatment on that ou... more When baseline risk of an outcome varies within a population, the effect of a treatment on that outcome will vary on at least one scale (e.g., additive, multiplicative). This treatment effect heterogeneity is of interest in patient-centered outcomes research. Based on a literature review and solicited expert opinion, we assert: 1) Treatment effect heterogeneity on the additive scale is most interpretable to healthcare providers and patients using effect estimates to guide treatment decision making; heterogeneity reported on the multiplicative scale may be misleading as to the magnitude or direction of a substantively important interaction. 2) The additive scale may give clues about sufficient-cause interaction, although such interaction is typically not relevant to patients' treatment choices. 3) Statistical modeling need not be conducted on the same scale as results are communicated. 4) Statistical testing is one tool for investigations, provided important subgroups are identified a priori, but test results should be interpreted cautiously given non-equivalence of statistical and clinical significance. 5) Qualitative interactions should be evaluated in a prespecified manner for important subgroups. Principled analytic plans that take into account the purpose of investigation of treatment effect heterogeneity are likely to yield more useful results for guiding treatment decisions.
Medical care, Jul 21, 2017
Fried and colleagues described a frailty phenotype measured in the Cardiovascular Health Study (C... more Fried and colleagues described a frailty phenotype measured in the Cardiovascular Health Study (CHS). This phenotype is manifest when ≥3 of the following are present: low grip strength, low energy, slowed waking speed, low physical activity, or unintentional weight loss. We sought to approximate frailty phenotype using only administrative claims data to enable frailty to be assessed without physical performance measures. We used the CHS cohort data linked to participants Medicare claims. The reference standard was the frailty phenotype measured at visits 5 and 9. With penalized logistic regression, we developed a parsimonious index for predicting the frailty phenotype using a linear combination of diagnoses, operationalized with claims data. We assessed the predictive validity of frailty index by examining how well it predicted common aging-related outcomes including hospitalization, disability, and death. There were 4454 CHS participants from 4 clinical sites. In total, 84% were wh...
American Journal of Epidemiology, 2016
Different phenotypes have increasingly been used as tools for clinical characterization of frailt... more Different phenotypes have increasingly been used as tools for clinical characterization of frailty among older adults. Although there have been studies about the comparability and effectiveness of various simplifications and approximations of existing frailty phenotypes for risk prediction, there have been no studies in which investigators evaluated the stability of the clinical characterization achieved. In the present study, we used baseline (1992-1996) data from 786 community-dwelling women who were 70-79 years of age in the Women's Health and Aging Study I and II to compare physical frailty phenotypes (PFPs). Using the 5 criteria set forth by Fried, we created 15 PFPs that were positive for various combinations of 3 or 4 of those criteria and compared them with the PFP that included all 5 criteria in order to assess construct validity with regard to frailty syndrome characterization and predictive validity for adverse outcomes of aging. All PFPs exhibited high specificity and negative predictive values for identifying frailty syndrome. Three-item PFPs were insensitive but were the best performers for positive predictive value, with the highest positive predictive value of 0.86 seen in the PFP characterized by the combination of weakness, exhaustion, and weight loss. In comparison, the 5-criterion PFP achieved a sensitivity of 0.82 but a positive predictive value of only 0.53. With regard to predictive validity, it was not merely the number of criteria used to characterize the PFPs but rather the specific criteria combinations that predicted the risk of adverse outcomes. Our findings show that there clinically important contexts in which simplified PFPs cannot be used interchangeably.
Journal of Statistical Software, 2009
We discuss R package BB, in particular, its capabilities for solving a nonlinear system of equati... more We discuss R package BB, in particular, its capabilities for solving a nonlinear system of equations. The function BBsolve in BB can be used for this purpose. We demonstrate the utility of these functions for solving: (a) large systems of nonlinear equations, (b) smooth, nonlinear estimating equations in statistical modeling, and (c) non-smooth estimating equations arising in rank-based regression modeling of censored failure time data. The function BBoptim can be used to solve smooth, box-constrained optimization problems. A main strength of BB is that, due to its low memory and storage requirements, it is ideally suited for solving high-dimensional problems with thousands of variables.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009
Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased com... more Background. Age-related deterioration in homeostatic regulatory mechanisms leads to decreased complexity in their output. For example, the degradation of cardiac autonomic control results in loss of complexity in the heart rate signal. Frailty is a state of critically impaired homeostasis that results in heightened vulnerability to stressors. We propose a new measure of heart rate variability (HRV) to capture the impairment in cardiac autonomic control associated with frailty. Methods. Traditional time and frequency domain indices of HRV were obtained from 2-hour ambulatory electrocardiograms (ECGs) of 276 women (65-101 years old) in the Women ' s Health and Aging Study-I. Principal components analysis was conducted on the correlation matrix of HRV indices. Frailty was defi ned using a validated instrument. Regression models were used to evaluate associations of HRV measures with age, frailty, and 5-year mortality. Results. The fi rst two principal components (PCs), PC1 and PC2, explained 90% of the variance in HRV indices. PC1 is the mean of log-transformed HRV indices. PC2 is a linear combination of log-transformed indices, with positive weights for very low frequency (VLF), low frequency (LF), and standard deviation of N-N intervals (SDNN), and negative weights for high frequency (HF), root-mean-squared differences of successive N-N intervals (RMSSD), and proportion of all N-N intervals that are larger than 50 ms (pNN50). Decreases in SDNN, VLF, LF, and LF/HF were associated with an increased risk of frailty. PC2 was more strongly associated with age (b = − .23, p < .001) and frailty (b = − .73, p < 10 − 5) than were the individual HRV indices and LF/HF. PC2 was also the best predictor of 5-year mortality (b = − .60, p < 10 − 6). Conclusions. Cardiac autonomic control, as refl ected by HRV, is impaired in frailty. A new measure derived from PC aggregation of traditional HRV indices provides a compact summary of this impairment.
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009
I t has been proposed that frailty, a syndrome of old age, results from an impairment across phys... more I t has been proposed that frailty, a syndrome of old age, results from an impairment across physiological systems (1) that leads to loss of homeostatic resilience. the hallmarks of this loss of integration of physiological function are increased susceptibility to stressors and even death. Because homeostatic resilience is inherently dynamic, losses are more likely to be unmasked as impaired ability to respond to a stressor than as a change in function under resting conditions. Frailty is thought to manifest a loss of physiological complexity as a qualitative change in the manner, not just a diminished amount, of response to stress via several physiological systems (2). However, this theory remains to be evaluated. Few frail older adults have been tested through stress tests, so the loss of function that would be evident from studying interactions among physiological systems under stress remains largely theoretical (3). A clinical phenotypic or operational definition of physical frailty composed of several components among weakness, slowness, low activity, exhaustion, and weight loss has been shown to have construct and predictive validity as evi-denced by its association with increased risk of future physical disability and death (4) and discriminant validity as a syndrome (5). Although frailty is thought to result from functional decline in several systems, including immunologic, hormonal, and neural (6,7), a central feature embedded in the frailty criteria is lower extremity exercise capacity (EC). We hypothesized that the systems involved in converting energy into lower extremity EC interact, that is, respond differently to each other in frail adults compared with non-frail adults. Identifying a difference in integrated function according to frailty status would contribute in previously unexplained ways to our current understanding of EC in late life. this study aimed to address these questions by: (a) determining the relationship between key physiological systems and EC in disabled older women, a cohort that provides an opportunity to study frailty but is underrepresented in physiology literature and (b) evaluating for interactions among these systems with frailty status with respect to their association with lower extremity EC obtained through a graded