Publications by authors named "Ravi Varadhan"

124 Publications

Life expectancy estimates based on comorbidities and frailty to inform preventive care.

J Am Geriatr Soc 2021 Sep 18. Epub 2021 Sep 18.

Department of Oncology, Division of Biostatistics and Bioinformatics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Long-term prognostication is important to inform preventive care in older adults. Existing prediction indices incorporate age and comorbidities. Frailty is another important factor in prognostication. In this project, we aimed at developing life expectancy estimates that incorporate both comorbidities and frailty.

Methods: In this retrospective cohort study, we used data from a 5% sample of Medicare beneficiaries with and without history of cancer from Surveillance, Epidemiology, and End Results (SEER) cancer registry areas. We included adults aged 66-95 years who were continuously enrolled in fee-for-service Medicare for ≥1 year from 1998 to 2014. Participants were followed for survival until 12/31/2015, death, or disenrollment. Comorbidity (none, low/medium, high) and frailty categories (low, high) were defined using established methods for claims. We estimated 5- and 10-year survival probabilities and median life expectancies by age, sex, comorbidities, and frailty.

Results: The study included 479,646 individuals (4,128,316 person-years), of whom most were women (58.7%). Frailty scores varied widely among participants in the same comorbidity category. In Cox models, both comorbidities and frailty were independent predictors of mortality. Individuals with high comorbidities (HR, 3.24; 95% CI, 3.20-3.28) and low/medium comorbidities (HR, 1.36; 95% CI, 1.34-1.39) had higher risks of death than those with no comorbidities. Compared to low frailty, high frailty was associated with higher risk of death (HR, 1.55; 95% CI, 1.52-1.58). Frailty affected life expectancy estimates in ways relevant to preventive care (i.e., distinguishing <10-year versus >10-year life expectancy) in multiple subgroups.

Conclusion: Incorporating both comorbidities and frailty may be important in estimating long-term life expectancies of older adults. Our life expectancy tables can aid clinicians' prognostication and inform simulation models and population health management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.17468DOI Listing
September 2021

Is Colorectal Cancer Screening Absolutely Beneficial for Older Adults?

JAMA Oncol 2021 Sep 16. Epub 2021 Sep 16.

Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2021.4152DOI Listing
September 2021

Risk Factors for Non-Resilient Outcomes in Older Adults after Total Knee Replacement in the FORCE-TJR Cohort.

J Gerontol A Biol Sci Med Sci 2021 Sep 4. Epub 2021 Sep 4.

The Division of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, Maryland.

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 non-resilient patient outcomes.

Methods: Secondary analysis of FORCE-TJR cohort study, a prospective registry of total joint replacement. Analysis included 7,239 adults ages 60 or older who underwent TKR between 2011- 2015. Measures included sociodemographic and health factors. Outcomes were categorized as physically resilient versus non-resilient based on the change from baseline to 1-year follow up for three patient-reported outcomes: the physical component summary (PCS), bodily pain (BP), and vitality (VT) from the Short Form-36 (SF-36) subcomponent scores, at pre-op and 1-year post-procedure. Associations were expressed as relative risk of physically non-resilient outcomes using generalized linear regression models, with Poisson distribution and log link.

Results: Age, BMI, and Charlson Comorbidity Index (CCI) were associated with increased risk of physically non-resilient outcomes across PCS, BP, and VT: age, per 5-years for PCS (RR=1.18[1.12-1.23]), BP (RR=1.06[1.01-1.11), and VT (RR=1.09[1.06-1.12]); BMI, per 5 Kg/m 2, for PCS (RR=1.13[1.07-1.19]), BP (RR=1.06[1.00-1.11]), and VT (RR=1.08[1.04-1.11]); and CCI for PCS CCI=1 (RR=1.38[1.20-1.59]), CCI=2-5 (RR=1.59[1.35-1.88]), CCI>=6 (RR=1.55[1.31-1.83]. Household-income >$45,000 associated with lower risk for PCS (RR=0.81[0.70-0.93]), BP (RR=0.80[0.69-0.91],), and VT (RR=0.86[0.78-0.93]).

Conclusions: We operationalized physical resilience and identified factors predicting resilience after TKR. This approach may aid clinical risk stratification, guide further investigation of causes, and ultimately aid patients through the design of interventions to enhance physical resilience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glab257DOI Listing
September 2021

The physical frailty syndrome as a transition from homeostatic symphony to cacophony.

Nat Aging 2021 Jan 14;1(1):36-46. Epub 2021 Jan 14.

Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. This Perspective synthesizes the evidence on the aging-related pathophysiology underpinning the clinical presentation of physical frailty as a phenotype of a clinical syndrome that is distinct from the cumulative-deficit-based frailty index. We focus on integrating the converging evidence on the conceptualization of physical frailty as a state, largely independent of chronic diseases, that emerges when the dysregulation of multiple interconnected physiological and biological systems crosses a threshold to critical dysfunction, severely compromising homeostasis. Our exegesis posits that the physiology underlying frailty is a critically dysregulated complex dynamical system. This conceptual framework implies that interventions such as physical activity that have multisystem effects are more promising to remedy frailty than interventions targeted at replenishing single systems. We then consider how this framework can drive future research to further understanding, prevention and treatment of frailty, which will likely preserve health and resilience in aging populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s43587-020-00017-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409463PMC
January 2021

Addressing and communicating heterogeneous treatment effects for patient subpopulations: Challenges and opportunities.

Authors:
Ravi Varadhan

Pharm Stat 2021 Sep 15;20(5):920-922. Epub 2021 Aug 15.

Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pst.2164DOI Listing
September 2021

Statins and cognitive decline in the Cardiovascular Health Study: A comparison of different analytical approaches.

J Gerontol A Biol Sci Med Sci 2021 Jul 31. Epub 2021 Jul 31.

Department of Epidemiology and Population Health, Stanford University, Stanford, CA.

Background: Despite their well-established benefits for the prevention of cardiovascular disease, robust evidence on the effects of statins on cognition is largely inconclusive. We apply various study designs and analytical approaches to mimic randomized controlled trial (RCT) effects from observational data.

Methods: We used observational data from 5,580 participants enrolled in the Cardiovascular Health Study from 1989/90 to 1999/2000. We conceptualized the cohort as an overlapping sequence of non-randomized trials. We compared multiple selection (eligible population, prevalent users, new-users) and analytic approaches (multivariable adjustment, inverse probability treatment weights, propensity score matching) to evaluate the association between statin use and 5-year change in global cognitive function, assessed using the Modified Mini-Mental State (3MS) examination.

Results: When comparing prevalent users to non-users (N=2,772), statin use was associated with slower cognitive decline over 5 years (adjusted annual change in 3MSE = 0.34 points/year; 95% CI:0.05;0.63). Compared to prevalent user design, estimates from new user designs (e.g. comparing eligible statin initiators to non-initiators) were attenuated showing either null or negative association, though not significant. For example, in a propensity score-matched sample of statin-eligible individuals (N=454), annual 3MS change comparing statin initiators to non-initiators was -0.21 points/year (95% CI:-0.81;0.39).

Conclusions: The association of statin use and cognitive decline is attenuated towards the null when using rigorous analytical approaches that more closely mimic RCTs. Point estimates, even within the same study, may vary depending on the analytical methods used. Further studies that leverage natural or quasi experiments around statin use are needed to replicate our findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glab220DOI Listing
July 2021

Allogeneic Blood or Marrow Transplantation with Nonmyeloablative Conditioning and High-Dose Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis for Secondary Central Nervous System Lymphoma.

Transplant Cell Ther 2021 Jul 20. Epub 2021 Jul 20.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.07.015DOI Listing
July 2021

Lasso estimation of hierarchical interactions for analyzing heterogeneity of treatment effect.

Stat Med 2021 Jul 8. Epub 2021 Jul 8.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

Individuals differ in how they respond to a given treatment. In an effort to predict the treatment response and analyze the heterogeneity of treatment effect, we propose a general modeling framework by identifying treatment-covariate interactions honoring a hierarchical condition. We construct a single-step norm penalty procedure that maintains the hierarchical structure of interactions in the sense that a treatment-covariate interaction term is included in the model only when either the covariate or both the covariate and treatment have nonzero main effects. We developed a constrained Lasso approach with two parameterization schemes that enforce the hierarchical interaction restriction differently. We solved the resulting constrained optimization problem using a spectral projected gradient method. We compared our methods to the unstructured Lasso using simulation studies including a scenario that violates the hierarchical condition (misspecified model). The simulations showed that our methods yielded more parsimonious models and outperformed the unstructured Lasso for correctly identifying nonzero treatment-covariate interactions. The superior performance of our methods are also corroborated by an application to a large randomized clinical trial data investigating a drug for treating congestive heart failure (N = 2569). Our methods provide a well-suited approach for doing secondary analysis in clinical trials to analyze heterogeneous treatment effects and to identify predictive biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/sim.9132DOI Listing
July 2021

Treatment of Acute Pain in Adults With Sickle Cell Disease in an Infusion Center Versus the Emergency Department : A Multicenter Prospective Cohort Study.

Ann Intern Med 2021 Sep 6;174(9):1207-1213. Epub 2021 Jul 6.

Oncology Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, Maryland (R.V.).

Background: Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs). Infusion centers (ICs) are alternatives to emergency department (ED) care and may improve patient outcomes.

Objective: To assess whether care in ICs or EDs leads to better outcomes for the treatment of uncomplicated VOCs.

Design: Prospective cohort. (ClinicalTrials.gov: NCT02411396).

Setting: 4 U.S. sites, with recruitment between April 2015 and December 2016.

Participants: Adults with SCD living within 60 miles of a study site.

Measurements: Participants were followed for 18 months after enrollment. Outcomes of interest were time to first dose of parenteral pain medication, whether pain reassessment was completed within 30 minutes after the first dose, and patient disposition on discharge from the acute care visit. Treatment effects for ICs versus EDs were estimated using a time-varying propensity score adjustment.

Results: Researchers enrolled 483 participants; the 269 who had acute care visits on weekdays are included in this report. With inverse probability of treatment-weighted adjustment, the mean time to first dose was 62 minutes in ICs and 132 minutes in EDs; the difference was 70 minutes (95% CI, 54 to 98 minutes; E-value, 2.8). The probability of pain reassessment within 30 minutes of the first dose of parenteral pain medication was 3.8 times greater (CI, 2.63 to 5.64 times greater; E-value, 4.7) in the IC than the ED. The probability that a participant's visit would end in admission to the hospital was smaller by a factor of 4 (0.25 [CI, 0.18 to 0.33]) with treatment in an IC versus an ED.

Limitation: The study was restricted to participants with uncomplicated VOCs.

Conclusion: In adults with SCD having a VOC, treatment in an IC is associated with substantially better outcomes than treatment in an ED.

Primary Funding Source: Patient-Centered Outcomes Research Institute.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M20-7171DOI Listing
September 2021

Geographic Regions Enriched with Frail Older Adults.

J Am Med Dir Assoc 2021 Jun 17. Epub 2021 Jun 17.

Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jamda.2021.05.029DOI Listing
June 2021

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia.

J Oncol Pharm Pract 2021 Jun 17:10781552211024727. Epub 2021 Jun 17.

The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/10781552211024727DOI Listing
June 2021

Gender-related differences in the outcomes and genomic landscape of patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.

Br J Haematol 2021 06 24;193(6):1142-1150. Epub 2021 May 24.

Division of Hematological Malignancies and Bone Marrow Transplantation, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes show a male predominance and men with MDS/MPN have worse outcomes, but it is unknown if the mutational burden differs between genders. We reviewed 167 patients with MDS/MPN and found that men had worse overall survival [hazard ratio (HR) 2·09, 95% confidence interval (CI) 1·16-3·75; P = 0·013] independent of subtype, Revised International Prognostic Scoring System score and age at diagnosis. We analysed the genomic data of a subset of 100 patients. Men had 0·88 more somatic mutations on average (95% CI 0·20-1·56, P = 0·011) independent of subtype, sample source and blast percentage. More somatic mutations was associated with a higher incidence of transformation to acute myeloid leukaemia (subdistribution HR 1·30, 95% CI 1·01-1·70; P = 0·046). Men had 0·70 more mutations in high-risk genes [additional sex combs like-1 (ASXL1), enhancer of zeste homolog 2 (EZH2), Runt-related transcription factor 1 (RUNX1), SET binding protein 1 (SETBP1), NRAS proto-oncogene, GTPase (NRAS), stromal antigen 2 (STAG2)] on average (95% CI 0·11-1·29, P = 0·021), and 13-times higher odds of harbouring an EZH2 mutation (95% CI 1·64-102·94, P = 0·015). The presence of an EZH2 mutation was associated with worse survival among men (HR 2·98, 95% CI 1·1-8·0; P = 0·031). Our present findings suggest that the worse outcomes in men with MDS/MPN are associated with a higher number of somatic mutations, especially in high-risk genes. These results warrant validation in larger cohorts and investigation of the underlying mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217263PMC
June 2021

Longitudinal Changes in Sex Hormone-Binding Globulin in Men With HIV.

J Acquir Immune Defic Syndr 2021 Aug;87(5):1178-1186

Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD.

Background: Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates sex hormone bioavailability and increases with age in the general population. SHBG concentrations are higher in people with HIV, a population in whom accelerated aging has been hypothesized. It is unclear whether longitudinal changes in SHBG increase over time and differ by HIV serostatus.

Methods: In a longitudinal study, SHBG was measured in 182 men with HIV (MWH) and 267 men without HIV (seronegative) from the Multicenter AIDS Cohort Study and matched for age, race, site, and time, with ≥2 SHBG serum samples over the 10 years after HAART initiation. Multivariable linear mixed-effects regression models were used to evaluate whether log-transformed SHBG [ln(SHBG)] and its rate of change differed by HIV serostatus.

Results: At baseline, the mean age in MWH was similar to that in HIV-seronegative men (51 ± 5 vs 49 ± 6 years). However, SHBG mean values were higher in MWH compared with those in HIV-seronegative men (65.6 ± 48.8 vs. 45.4 ± 22 nmol/L, P < 0.001). In a fully adjusted model, SHBG increased over time and at a faster rate in MWH compared with that in HIV-seronegative men: [2.0%/year (95% CI: 1.4 to 2.7) vs 1.3%/year (95% CI: 0.8 to 1.8), respectively, P = 0.038]. Among MWH, higher SHBG concentrations were significantly associated with lower CD4+ T-cell count [β= -0.02 (95% CI: -0.03 to -0.0002), P < 0.05], fewer cumulative years on zidovudine [β = -0.027 (95% CI: -0.045 to -0.009), P < 0.001], and greater cumulative years on nonnucleoside reverse transcriptase inhibitors drugs [β = 0.022 (95% CI: 0.0006 to 0.04), P < 0.05].

Conclusions: Aging-related increases in SHBG were faster in MWH compared with those in HIV-seronegative men and were related to poorer immunologic status and antiretroviral medication exposure. The mechanisms and consequences of these findings require further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263509PMC
August 2021

Assessing and communicating heterogeneity of treatment effects for patient subpopulations: Keynote and panel discussion on communicating heterogeneous treatment effects across populations.

Pharm Stat 2021 Sep 4;20(5):965-978. Epub 2021 May 4.

Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

How do we communicate nuanced regulatory information to different audiences, recognizing that the consumer audience is very different from the physician audience? In particular, how do we communicate the heterogeneity of treatment effects - the potential differences in treatment effects based on sex, race, and age? That is a fundamental question at the heart of this panel discussion. Each panelist addressed a specific "challenge question" during their 5-minute presentation, and the list of questions is provided. The presentations were followed by a question and answer session with members of the audience and the panelists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pst.2123DOI Listing
September 2021

Large Granular Lymphocytosis With Cytopenias After Allogeneic Blood or Marrow Transplantation: Clinical Characteristics and Response to Immunosuppressive Therapy.

Transplant Cell Ther 2021 03 16;27(3):260.e1-260.e6. Epub 2020 Dec 16.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Large granular lymphocytosis (LGL)-or LGL leukemia-is a T- or NK-cell lymphoproliferative disorder that often results in cytopenias and autoimmune phenomena. Several studies have described LGL in a subset of patients after allogeneic blood or marrow transplantation (alloBMT), almost exclusively in the setting of asymptomatic lymphocytosis. Some have suggested an association with improved transplant-related outcomes. In contrast, clinically significant LGL after alloBMT is only described in small case reports. This study sought to assess the characteristics, significance, and response to treatment of LGL associated with unexplained anemia, thrombocytopenia, or neutropenia after alloBMT. We performed a retrospective analysis of 150 patients who were evaluated for LGL by peripheral blood flow cytometry (LGL flow) for unexplained cytopenias following initial engraftment after alloBMT from January 1 2012 to July 1, 2019. We identified patients with abnormally increased populations of LGL cells (LGL+) as assessed by Johns Hopkins Hematopathology. We collected demographic, transplantation, and LGL treatment information from electronic medical records. We compared LGL+ patients to patients with unexplained cytopenias with negative flow cytometry for LGL (LGL-) in this cohort. We also assessed change in blood counts after 4 weeks of immunosuppressive therapy in LGL+ patients. Cytopenias occurred at a median of 5.7 months (range 1-81) after alloBMT. The majority of the transplants were nonmyeloablative from haploidentical donors, and all patients received post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis, consistent with the overall alloBMT characteristics at our center. We identified 70 patients with LGL and cytopenias, representing 47% of those evaluated by flow cytometry. There were no significant demographic or transplant-related differences between LGL+ patients and LGL- patients. The median age was 59, and 63% were male. LGL+ patients were more likely to have had cytomegalovirus (CMV) viremia (73% versus 28%, P < .0001), but not acute or chronic graft-versus-host disease. LGL+ patients had higher absolute lymphocyte counts (1500 versus 485/ mm, P < .0001), a trend toward lower absolute neutrophil count (660 versus 965/mm, P = .17), and lower neutrophil to lymphocyte ratio (0.39 versus 1.71, P < .001). There were no differences in overall survival or relapse-free survival. Of those with T-cell LGL, 45 were assessed for T-cell receptor clonality. In all, 22% were clonal, 53% oligoclonal, 4% polyclonal, and 20% indeterminate. Thirty (43%) LGL+ patients received immunosuppressive therapy (IST) for cytopenias. First-line treatment was corticosteroids for 25 (83%). Among those treated, there was an increase in median absolute neutrophil count from 720 before treatment to 1990/mm after 4 weeks (P = .0017). Thrombocytopenia and anemia showed at most a mild improvement with IST. LGL was a common association with otherwise unexplained cytopenias after alloBMT, almost always after prior CMV infection. LGL in the setting of cytopenias did not predict improved transplantation outcomes compared to those with cytopenias without presence of LGL. IST was effective at improving neutropenia associated with LGL after alloBMT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2020.12.008DOI Listing
March 2021

Relationship of donor age and relationship to outcomes of haploidentical transplantation with posttransplant cyclophosphamide.

Blood Adv 2021 03;5(5):1360-1368

Department of Oncology and.

Allogeneic blood or marrow transplantation (BMT) physicians seek to optimize all possible variables to improve outcomes. Selectable factors include conditioning, graft-versus-host disease (GVHD) prophylaxis, graft source, and donor. Many patients, especially those with eligible haploidentical (haplo) donors, will have multiple donor options. We seek to identify factors to optimize the choice of haplo donors when using posttransplantation cyclophosphamide (PTCy) GVHD prophylaxis. We evaluated the effect of modifiable donor characteristics (donor age and relationship) on outcomes following haplo BMT with a uniform nonmyeloablative conditioning and PTCy. From 2002 to 2017, 889 consecutive adult patients underwent nonmyeloablative haplo BMT with PTCy. Median follow-up among survivors was 2.5 years after BMT. Median recipient age was 59 (range: 18 to 76) years and median donor age was 40 (range: 13 to 79) years. Multivariable analyses demonstrated that increasing donor age by decade was associated with poorer overall survival (hazard ratio [HR], 1.13 [1.05, 1.22; P = .0015]), worse progression-free survival (HR, 1.09 [1.02, 1.16; P = .015]), and a higher risk for grade 2 to 4 and grade 3 to 4 GVHD (1.3 [1.06, 1.61; P = .013]), but not for chronic GVHD (HR, 1.06 [0.94, 1.2]; P = .37). These less-favorable results with older donors were attributable to worse nonrelapse mortality (HR, 1.19 [1.05, 1.34]; P = .006), not relapse. Parents were associated with inferior outcomes compared with sibling donors, whereas no significant differences were observed between parental donors. These data suggest that the youngest, adult-sized donors should be preferred when multiple haplo donors are available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948266PMC
March 2021

Developing Workshops to Enhance Hope Among Patients With Metastatic Breast Cancer and Oncologists: A Pilot Study.

JCO Oncol Pract 2021 06 17;17(6):e785-e793. Epub 2021 Feb 17.

Shaare Zedek Medical Center, Jerusalem, Israel.

Purpose: Hope is a modifiable entity that can be augmented. We evaluated the feasibility, acceptability, and efficacy of a short intervention to increase hopefulness in patients with advanced breast cancer and oncologists.

Methods: We enrolled eligible participants to two cohorts: one for patients with metastatic breast cancer and one for medical, radiation, or surgical oncologists. The intervention, a half-day hope enhancement workshop, included groups of 10-15 participants within each cohort. Participants in both cohorts completed preworkshop, postworkshop, and 3-month evaluations, which included the Adult Hope Scale (AHS), Herth Hope Index (HHI), and Patient-Reported Outcomes Measurement Information System-Global Health (PROMIS-GH) measures in patients, and the AHS, HHI, and a burnout self-assessment tool in physicians.

Results: We consented 13 patients and 26 oncologists for participation in the workshop and 76.9% (n = 10) of consented patients and 100% (n = 26) of consented physicians participated. Postworkshop, all participants planned to incorporate what they learned into their daily lives. In patients, AHS scores increased from preworkshop to postworkshop, and the mean change of 5.90 was significant (range 0-15, SD: 4.7, = 3.99, = .0032). HHI scores also increased, although the mean change was not significant. AHS and HHI scores did not significantly change in oncologists from preworkshop to postworkshop. At 3 months, less than half of the participants responded to the evaluation.

Conclusion: We found that conducting a hope-enhancement workshop for patients with metastatic breast cancer and oncologists was feasible, generally acceptable to both populations, and associated with increased hopefulness in patients. Next steps should focus on confirming this effect in a randomized study and maintaining this effect in the postworkshop interval.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/OP.20.00744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258015PMC
June 2021

A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML.

Front Oncol 2020 23;10:587062. Epub 2020 Oct 23.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids . We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line . These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. clinicaltrials.gov, identifier NCT02749708.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.587062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645224PMC
October 2020

Thrombotic Microangiopathy after Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

Biol Blood Marrow Transplant 2020 12 19;26(12):2306-2310. Epub 2020 Sep 19.

Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, Maryland.

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686062PMC
December 2020

Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses.

CMAJ 2020 Aug;192(32):E901-E906

Departments of Health Research Methods, Evidence, and Impact (Schandelmaier, Briel, Walsh, Thabane, Guyatt), Medicine (Walsh, Guyatt), Pediatrics (Thabane) and Anesthesia (Thabane), McMaster University, Hamilton, Ont.; Institute for Clinical Epidemiology and Biostatistics (Schandelmaier, Briel), Department of Clinical Research, Basel University, Basel, Switzerland; Division of Biostatistics and Bioinformatics (Varadhan), Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Md.; Department of Biostatistics (Schmid), Brown University School of Public Health, Brown University, Providence, RI; Indian institute of Public Health-Delhi (Devasenapathy), Public Health Foundation of India, New Delhi, India; VA Center for Clinical Management and Research (Hayward); Department of Internal Medicine (Hayward), University of Michigan School of Medicine; Department of Orthopaedic Surgery (Gagnier), University of Michigan; Department of Epidemiology (Gagnier), School of Public Health, University of Michigan, Ann Arbor, Mich.; Biostat (Borenstein), Englewood, NJ; Department of Social Dentistry (van der Heijden), Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Amsterdam, Netherlands; Center for Evidence Synthesis in Health (Dahabreh) and Departments of Health Services, Policy, and Practice (Dahabreh) and Epidemiology (Dahabreh), School of Public Health, Brown University, Providence, RI; Chinese Evidence-Based Medicine Center (Sun), West China Hospital, Sichuan University, Chengdu, China; Institute of Medical Biometry and Statistics (Sauerbrei), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Population Health Research Institute (Walsh), Hamilton Health Sciences/McMaster University, Hamilton, Ont.; Departments of Medicine (Ioannidis), Health Research and Policy (Ioannidis) and Biomedical Data Science (Ioannidis), and Statistics and Meta-Research Innovation Center at Stanford (METRICS) (Ioannidis), Stanford University, Stanford, Calif.; Biostatistics Unit (Thabane), St. Joseph's Healthcare, Hamilton, Ont.

Background: Most randomized controlled trials (RCTs) and meta-analyses of RCTs examine effect modification (also called a subgroup effect or interaction), in which the effect of an intervention varies by another variable (e.g., age or disease severity). Assessing the credibility of an apparent effect modification presents challenges; therefore, we developed the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN).

Methods: To develop ICEMAN, we established a detailed concept; identified candidate credibility considerations in a systematic survey of the literature; together with experts, performed a consensus study to identify key considerations and develop them into instrument items; and refined the instrument based on feedback from trial investigators, systematic review authors and journal editors, who applied drafts of ICEMAN to published claims of effect modification.

Results: The final instrument consists of a set of preliminary considerations, core questions (5 for RCTs, 8 for meta-analyses) with 4 response options, 1 optional item for additional considerations and a rating of credibility on a visual analogue scale ranging from very low to high. An accompanying manual provides rationales, detailed instructions and examples from the literature. Seventeen potential users tested ICEMAN; their suggestions improved the user-friendliness of the instrument.

Interpretation: The Instrument for assessing the Credibility of Effect Modification Analyses offers explicit guidance for investigators, systematic reviewers, journal editors and others considering making a claim of effect modification or interpreting a claim made by others.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1503/cmaj.200077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829020PMC
August 2020

Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: A Retrospective Cohort Study.

Biol Blood Marrow Transplant 2020 09 24;26(9):1679-1688. Epub 2020 Jun 24.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland.. Electronic address:

: Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis.  : We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy.  : We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P = .17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P = .05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD.  : ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486273PMC
September 2020

Cortisol and Dehydroepiandrosterone Response to Adrenocorticotropic Hormone and Frailty in Older Women.

J Gerontol A Biol Sci Med Sci 2021 04;76(5):901-905

Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia.

Background: The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old adults and may provide insight into the physiologic response to stress.

Method: We performed a standard 250 µg ACTH stimulation test in a home-based substudy of 51 women aged 85-96 years enrolled in the Women's Health and Aging Study II who were not taking corticosteroids. We examined the cortisol and dehydroepiandrosterone (DHEA) responses at 0, 30, 60, and 120 minutes, overall and by frailty status.

Results: The peak cortisol response to ACTH could not be determined, with the highest levels at the 120-minute time point. Pre- and post-ACTH stimulated cortisol levels did not differ by frailty status over this time frame, with no difference in the characteristics of the dose-response curves. Pre- and post-ACTH stimulated DHEA levels also did not differ by frailty status, though the dose-response curves suggested divergence after stimulation, with a more rapid DHEA response with increasing frailty.

Conclusions: Our data demonstrate a robust cortisol response to ACTH challenge testing, but inadequate negative feedback in old-old women, resulting in prolonged exposure to cortisol. Future studies should examine dynamic cortisol and DHEA responses in this age group, using a less potent ACTH stimulus and longer collection period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087274PMC
April 2021

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Ann Intern Med 2020 06;172(11):776

Tufts Medical Center, Boston, MA (D.M.K.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/L20-0427DOI Listing
June 2020

Derivation of a measure of physiological multisystem dysregulation: Results from WHAS and health ABC.

Mech Ageing Dev 2020 06 11;188:111258. Epub 2020 May 11.

Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Introduction: Multifactorial biological processes underpin dysregulation over several individual physiological systems. However, it is challenging to characterize and model this multisystemic dysregulation and its relationship with individual physiologic systems. We operationalized a theory-driven measure of multisystem dysregulation and empirically tested for measurement differences by key characteristics.

Methods: We used the Women's Health and Aging Studies (WHAS) I and II (N = 649), and the Health ABC study (N = 1515). Twelve biomarkers representing multiple systems including stress response (e.g., inflammation), endocrine system, and energy regulation were identified. A series of confirmatory factor analyses (CFA) were conducted to evaluate the interplay between physiological systems and underlying multisystem dysregulation. We evaluated convergent criterion validity of a score for multisystem dysregulation against the physical frailty phenotype, and predictive criterion validity with incidence of walking difficulty and mortality.

Results: A bifactor CFA, a model in which dysregulation of individual systems proceeds independently of generalized dysregulation, fit data well in WHAS (RMSEA: 0.019; CFI: 0.977; TLI: 0.961) and Health ABC (RMSEA: 0.047; CFI: 0.874; TLI: 0.787). The general dysregulation factor was associated with frailty (OR: 2.2, 95 % CI: 1.4, 3.5), and elevated risk of incident walking difficulty and mortality. Findings were replicated in Health ABC.

Discussion: Biomarker data from two epidemiologic studies support the construct of multisystem physiological dysregulation. Results further suggest system-specific and system-wide processes have unique and non-overlapping contributions to dysregulation in biological markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2020.111258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375911PMC
June 2020

Modeling of Clinical Phenotypes Assessed at Discrete Study Visits.

Epidemiol Methods 2019 Dec 2;8(1). Epub 2019 Aug 2.

Department of Mental Health, Johns Hopkins University, Bloomberg School of Public Health.

In studies of clinical phenotypes, such as dementia, disability, and frailty, participants are typically assessed at in-person clinic visits. Thus, the precise time of onset for the phenotype is unknown. The discreteness of the clinic visits yields grouped event time data. We investigate how to perform a risk factor analysis in the case of grouped data. Since visits can be months to years apart, numbers of ties can be large, causing the exact tie-handling method of the Cox model to be computationally infeasible. We propose two, new, computationally efficient approximations to the exact method: Laplace approximation and an analytic approximation. Through extensive simulation studies, we compare these new methods to the Prentice-Gloeckler model and the Cox model using Efron's and Breslow's tie-handling methods. In addition, we compare the methods in an application to a large cohort study ( = 3,605) on the development of clinical frailty in older adults. In our simulations, the Laplace approximation has low bias in all settings, and the analytic approximation has low bias in settings where the regression coefficient is not large in magnitude. Their corresponding confidence intervals also have approximately the nominal coverage probability. In the data application, the results from the approximations are nearly identical to that of the Prentice-Gloeckler model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/em-2018-0011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806193PMC
December 2019

Allogeneic Haploidentical Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide in Chronic Lymphocytic Leukemia.

Biol Blood Marrow Transplant 2020 03 12;26(3):502-508. Epub 2019 Nov 12.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Allogeneic blood or marrow transplantation (allo-BMT) remains the only treatment for chronic lymphocytic leukemia (CLL) with curative potential. Although post-transplantation cyclophosphamide (PTCy) reduces allo-BMT toxicity by decreasing the risk of graft-versus-host disease (GVHD), its effect on CLL allo-BMT outcomes is unknown. We studied 64 consecutive patients with CLL who underwent nonmyeloablative (NMA) haploidentical allo-BMT at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. In this cohort, the 4-year overall survival was 52% (95% confidence interval [CI], 40% to 68%), and progression-free survival was 37% (95% CI, 26% to 54%). Six patients experienced engraftment failure. PTCy prophylaxis was associated with a modest cumulative incidence of 1-year grade II-IV acute GVHD (27%; %95% CI, 15% to 38%) and %%%2-year chronic GVHD (17%; 95% CI, 7% to 26%). We demonstrate that NMA haploidentical allo-BMT with PTCy is a safe and effective treatment option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.11.008DOI Listing
March 2020

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Ann Intern Med 2020 01 12;172(1):35-45. Epub 2019 Nov 12.

Leiden University Medical Center, Leiden, the Netherlands (E.W.S.).

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M18-3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531587PMC
January 2020

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration.

Ann Intern Med 2020 01 12;172(1):W1-W25. Epub 2019 Nov 12.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M18-3668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750907PMC
January 2020

A Socratic Inquiry Into the Nature of Frailty.

Authors:
Ravi Varadhan

J Am Geriatr Soc 2019 12 24;67(12):2455-2457. Epub 2019 Oct 24.

Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

In Plato's dialogues, Socrates, the protagonist, attempts to bring out the essential nature of an idea or a concept by engaging in a dialogue with the other characters. He asks probing questions of them to challenge their unquestioned assumptions and to eliminate flaws in their thinking. A hallmark of the dialogues is that Socrates himself never provides a final answer regarding the nature of the idea under discussion. Inspired by the power of the Socratic model to illumine one's thinking on difficult concepts, we have developed a short dialogue examining the nature of geriatric frailty. Our goal is to communicate, in a lively and nontechnical style, some of the fundamental challenges in studying frailty in older adults. Those acquainted with Plato's dialogues will recognize the resemblance to the initial segment of The Republic, which takes place in the house of a wealthy merchant named Cephalus. J Am Geriatr Soc 67:2455-2457, 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.16207DOI Listing
December 2019
-->