R I Horwitz

Stanford University, Palo Alto, California, United States

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Publications (223)3265.49 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Patients with severe hypertriglyceridemia have an increased risk of cardiovascular disease and pancreatitis. Target triglyceride levels associated with clinical benefit for patients with severe hypertriglyceridemia are not currently known. This study evaluates the association between lower follow-up triglyceride levels and incidence of clinical events for patients with severe hypertriglyceridemia. Methods By using claims data from 2 large US healthcare databases, we conducted a retrospective cohort study and identified 41,210 adults with severe hypertriglyceridemia (triglycerides ≥500 mg/dL) between June 2001 and September 2010. The date of the first severe hypertriglyceridemia laboratory result was the index date. Patients were categorized into 1 of 5 triglyceride ranges (<200 mg/dL, 200-299 mg/dL, 300-399 mg/dL, 400-499 mg/dL, and ≥500 mg/dL) based on a follow-up triglyceride level assessed 6 to 24 weeks after initial triglyceride levels were measured. Adjusted Cox regression models were developed to evaluate the impact of follow-up triglyceride levels on rates of pancreatitis episodes and cardiovascular events. Results The mean age of patients was 50 years, 72% were male, and the mean follow-up was 825 days. Patients with severe hypertriglyceridemia with follow-up triglyceride levels <200 mg/dL experienced a lower rate of pancreatitis episodes (adjusted incidence rate ratio, 0.45; 95% confidence interval, 0.34-0.60) and cardiovascular events (adjusted incidence rate ratio, 0.71; 95% confidence interval, 0.64-0.78) with some clinical benefit in adults with severe hypertriglyceridemia with follow-up triglyceride levels 200 to 299 mg/dL and 300 to 399 mg/dL (P < .001 for trend). Conclusions We observed the greatest impact on clinical events among patients with severe hypertriglyceridemia with the lowest follow-up triglyceride levels.
    The American journal of medicine 01/2014; 127(1):36–44.e1. DOI:10.1016/j.amjmed.2013.09.018 · 5.00 Impact Factor
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    ABSTRACT: To ensure that clinical research arrives at the "right" answers to the right questions for patients, studies should be designed to more closely approximate real-world use of therapeutics and devices.
    Science translational medicine 01/2014; 6(221):221fs5. DOI:10.1126/scitranslmed.3007649 · 15.84 Impact Factor
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    ABSTRACT: Frailty is a multidimensional phenotype that describes declining physical function and a vulnerability to adverse outcomes in the setting of physical stress such as illness or hospitalization. Phase angle is a composite measure of tissue resistance and reactance measured via bioelectrical impedance analysis (BIA). Whether phase angle is associated with frailty and mortality in the general population is unknown. To evaluate associations among phase angle, frailty and mortality. Population-based survey. Third National Health and Nutritional Examination Survey (1988-1994). In all, 4,667 persons aged 60 and older. Frailty was defined according to a set of criteria derived from a definition previously described and validated. Narrow phase angle (the lowest quintile) was associated with a four-fold higher odds of frailty among women and a three-fold higher odds of frailty among men, adjusted for age, sex, race-ethnicity and comorbidity. Over a 12-year follow-up period, the adjusted relative hazard for mortality associated with narrow phase angle was 2.4 (95 % confidence interval [95 % CI] 1.8 to 3.1) in women and 2.2 (95 % CI 1.7 to 2.9) in men. Narrow phase angle was significantly associated with mortality even among participants with little or no comorbidity. Analyses of BIA and frailty were cross-sectional; BIA was not measured serially and incident frailty during follow-up was not assessed. Participants examined at home were excluded from analysis because they did not undergo BIA. Narrow phase angle is associated with frailty and mortality independent of age and comorbidity.
    Journal of General Internal Medicine 09/2013; 29(1). DOI:10.1007/s11606-013-2585-z · 3.42 Impact Factor
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    ABSTRACT: To investigate the relationship among parity, length of the inter-pregnancy intervals and excessive pregnancy weight gain in the first pregnancy and the risk of obesity. Using a prospective cohort study of 3,422 non-obese, non-pregnant US women aged 14-22 years at baseline, adjusted Cox models were used to estimate the association among parity, inter-pregnancy intervals, and excessive pregnancy weight gain in the first pregnancy and the relative hazard rate (HR) of obesity. Compared to nulliparous women, primiparous women with excessive pregnancy weight gain in the first pregnancy had a HR of obesity of 1.79 (95 % CI 1.40, 2.29); no significant difference was seen between primiparous without excessive pregnancy weight gain in the first pregnancy and nulliparous women. Among women with the same pregnancy weight gain in the first pregnancy and the same number of inter-pregnancy intervals (12 and 18 months or ≥18 months), the HR of obesity increased 2.43-fold (95 % CI 1.21, 4.89; p = 0.01) for every additional inter-pregnancy interval of <12 months; no significant association was seen for longer inter-pregnancy intervals. Among women with the same parity and inter-pregnancy interval pattern, women with excessive pregnancy weight gain in the first pregnancy had an HR of obesity 2.41 times higher (95 % CI 1.81, 3.21; p < 0.001) than women without. Primiparous and nulliparous women had similar obesity risk unless the primiparous women had excessive pregnancy weight gain in the first pregnancy, then their risk of obesity was greater. Multiparous women with the same excessive pregnancy weight gain in the first pregnancy and at least one additional short inter-pregnancy interval had a significant risk of obesity after childbirth. Perinatal interventions that prevent excessive pregnancy weight gain in the first pregnancy or lengthen the inter-pregnancy interval are necessary for reducing maternal obesity.
    Maternal and Child Health Journal 04/2013; 18(3). DOI:10.1007/s10995-013-1272-3 · 2.24 Impact Factor
  • Ralph I Horwitz · Mark R Cullen · Jill Abell · Jennifer B Christian
    Science 03/2013; 339(6124):1155-6. DOI:10.1126/science.1234106 · 33.61 Impact Factor
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    ABSTRACT: The bedside evaluation, consisting of the history and physical examination, was once the primary means of diagnosis and clinical monitoring. The recent explosion of imaging and laboratory testing has inverted the diagnostic paradigm. Physicians often bypass the bedside evaluation for immediate testing and therefore encounter an image of the patient before seeing the patient in the flesh. In addition to risking delayed or missed diagnosis of readily recognizable disease, physicians who forgo or circumvent the bedside evaluation risk the loss of an important ritual that can enhance the physician-patient relationship. Patients expect that some form of bedside evaluation will take place when they visit a physician. When physicians complete this evaluation in an expert manner, it can have a salutary effect. If done poorly or not at all, in contrast, it can undermine the physician-patient relationship. Studies suggest that the context, locale, and quality of the bedside evaluation are associated with neurobiological changes in the patient. Recognizing the importance of the bedside evaluation as a healing ritual and a powerful diagnostic tool when paired with judicious use of technology could be a stimulus for the recovery of an ebbing skill set among physicians.
    Annals of internal medicine 10/2011; 155(8):550-3. DOI:10.1059/0003-4819-155-8-201110180-00013 · 17.81 Impact Factor
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    ABSTRACT: Concerned with the quality of internal medicine training, many leaders in the field assembled to assess the state of the residency, evaluate the decline in interest in the specialty, and create a framework for invigorating the discipline. Although many external factors are responsible, we also found ourselves culpable: allowing senior role models to opt out of important training activities, ignoring a progressive atrophy of bedside skills, and focusing on lock-step curricula, lectures, and compiled diagnostic and therapeutic strategies. The group affirmed its commitment to a vision of internal medicine rooted in science and learned with mentors at the bedside. Key factors for new emphasis include patient-centered small group teaching, greater incorporation of clinical epidemiology and health services research, and better schedule control for trainees. Because previous proposals were weakened by lack of evidence, we propose to organize the Cooperative Educational Studies Group, a pool of training programs that will collect a common data set describing their programs, design interventions to be tested rigorously in multi-methodological approaches, and at the same time produce knowledge about high-quality practice.
    The American journal of medicine 09/2011; 124(9):806-12. DOI:10.1016/j.amjmed.2011.03.007 · 5.00 Impact Factor
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    ABSTRACT: Clinical trials of stroke therapy have been hampered by slow rates of enrolment. Our purpose is to validate a previously developed model for accelerating enrolment in clinical trials by replicating it at new locations. The model employs coordinators who travel from a host institution to enrol participants from a network of participating hospitals. Active surveillance assures identification of all eligible patients. Among 70 U.S. investigators participating in National Institutes of Health-funded trial of stroke prevention, five investigators were invited to develop local identification and outreach networks (LIONs). Each LION comprised a LION coordinating centre servicing multiple hospitals. Hospitals provided names of patients with stroke or transient ischaemic attack to researchers at the LION coordinating centre who initiated contact; patients were offered home visits for consent and randomization. Outcomes were feasibility, enrolment, data quality, and cost. Five LIONs varied in size from two to eight hospitals. All 24 hospitals we approached agreed to participate. The average monthly rate of enrolment at the research sites increased from 1.4 participants to 3.5 after expanding from a single institution model to the LION format (mean change = 2.1, range 0.9-3.7). Monthly performance improved over time. Data quality was similar for LIONs and non-LION sites, except for drug adherence which was lower at LIONs. The average cost to randomize and follow one participant during the study interval was 2.4 times the cost under the per-patient, cost-reimbursement strategy at non-LION sites. The cost ratio declined from 3.4 in year one to 1.8 in year two. The LION strategy requires unprecedented collaboration and trust among institutions. Applicability beyond stroke requires confirmation. LIONs are a practical, reproducible method to increase enrolment in trial research. Twelve months were required for the average site to reach its potential. The per-participant cost at LIONs was higher than conventional sites but declined over time.
    Clinical Trials 08/2011; 8(5):645-53. DOI:10.1177/1740774511414925 · 1.93 Impact Factor
  • RA Marrie · R Horwitz · G Cutter · T Tyry
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    ABSTRACT: Little is known about the impact of comorbidity on health-related quality of life (HRQOL) in multiple sclerosis (MS). We investigated the association of comorbidity and health-related HRQOL among participants in the North American Research Committee on Multiple Sclerosis (NARCOMS). In 2006, we queried NARCOMS participants regarding physical and mental comorbidities and HRQOL, using the Short-Form 12. We summarized physical HRQOL using the aggregate Physical Component Scale (PCS-12) score and mental HRQOL using the aggregate Mental Component Scale (MCS-12) score. We assessed multivariable associations between comorbidity and HRQOL using a general linear model, adjusting for potential confounders. Among 8983 respondents, the mean (SD) PCS-12 was 36.9 (11.8) and MCS-12 was 45.6 (11.6). After adjustment for sociodemographic and clinical factors, participants with any physical comorbidity had a lower PCS-12 (37.2; 95% CI: 36.4-38.1) than those without any physical comorbidity (40.1; 95% CI: 39.0-41.1). As the number of physical comorbidities increased, PCS-12 scores decreased (r = -0.25; 95% CI: -0.23 to -0.27) indicating lower reported HRQOL. Participants with any mental comorbidity had a lower MCS-12 (40.7; 95% CI: 39.8-41.6) than those without any mental comorbidity (48.5; 95% CI: 47.7-49.4). Comorbidity is associated with reduced HRQOL in MS. Further research should evaluate whether more aggressive treatment of comorbidities improves the HRQOL of MS patients.
    Acta Neurologica Scandinavica 05/2011; 125(3):180-6. DOI:10.1111/j.1600-0404.2011.01526.x · 2.40 Impact Factor
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    Benjamin J Seligman · Mark R Cullen · Ralph I Horwitz
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    ABSTRACT: The World Health Organization's Global Burden of Disease (GBD) reports are an important tool for global health policy makers, however the accuracy of estimates for countries undergoing an epidemiologic transition is unclear. We attempted to validate the life table model used to generate estimates for all-cause mortality in developing countries. Data were obtained for males and females from the Human Mortality Database for all countries with available data every ten years from 1900 to 2000. These provided inputs for the GBD life table model and served as comparison observed data. Above age sixty model estimates of survival for both sexes differed substantially from those observed. Prior to the year 1960 for males and 1930 for females, estimated survival tended to be greater than observed; following 1960 for both males and females estimated survival tended to be less than observed. Viewing observed and estimated survival separately, observed survival past sixty increased over the years considered. For males, the increase was from a mean (sd) probability of 0.22 (0.06) to 0.46 (0.1). For females, the increase was from 0.26 (0.06) to 0.65 (0.08). By contrast, estimated survival past sixty decreased over the same period. Among males, estimated survival probability declined from 0.54 (0.2) to 0.09 (0.06). Among females, the decline was from 0.36 (0.12) to 0.15 (0.08). These results show that the GBD mortality model did not accurately estimate survival at older ages as developed countries transitioned in the twentieth century and may be similarly flawed in developing countries now undergoing transition. Estimates of the size of older-age populations and their attributable disease burden should be reconsidered.
    PLoS ONE 05/2011; 6(5):e20264. DOI:10.1371/journal.pone.0020264 · 3.23 Impact Factor
  • International Stroke Conference; 03/2011
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    ABSTRACT: Smoking is a risk factor for multiple sclerosis (MS) and autoimmune disease, and might explain an increased risk of comorbid autoimmune disease (CAD) in MS. We compared the risk of CAD in smokers and nonsmokers with MS. Participants enrolled in the North American Research Committee on Multiple Sclerosis Registry reported their smoking status, the presence of CAD and the year of diagnosis. We used multivariable logistic regression to determine the independent association between smoking and CAD. We also compared the risk of developing a CAD in current smokers versus never-smokers who did not report any CAD at MS onset, using a proportional hazards model. Among 8,875 participants reporting comorbidities and smoking status, 1,649 (18.5%) reported a CAD. In a multivariable logistic model, ever-smokers had increased odds of reporting a CAD (odds ratio: 1.22; 95% CI: 1.08-1.38). Among the 7,830 participants without a CAD at onset of MS who reported their smoking status, including the age at which they started smoking, 3,035 (36.8%) currently smoked, while 3,805 (48.6%) never smoked. After adjustment, smokers had an increased risk of developing any autoimmune disease (hazard ratio: 1.23; 95% CI: 1.08-1.41) after MS onset. Smoking is associated with an increased risk of CAD in MS.
    Neuroepidemiology 02/2011; 36(2):85-90. DOI:10.1159/000323948 · 2.56 Impact Factor
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    Esa M Davis · Kurt C Stange · Ralph I Horwitz
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    ABSTRACT: The perinatal period, from early in the first trimester to 1 year postpartum, provides opportunities for novel public health interventions to reduce obesity disparities. We present a unifying socio-biological framework to suggest opportunities for multidisciplinary research and public health approaches to elucidate and target the mechanisms for the development of maternal obesity and related disparities. The framework illustrates the interplay of the social, cultural and physical environment; stress appraisal and response; and coping behaviors on short-term outcomes (e.g. allostatic load and gestational weight gain), the intermediate outcomes of persistent insulin resistance and post-partum weight retention, and longer term outcomes of obesity and its disease consequences. Testing the proposed relationships may provide insights into how childbearing risk factors such as gestational weight gain, postpartum weight retention and parity contribute to obesity, which are needed to inform public health policies and clinical care guidelines aimed at reducing obesity and improving the health of women.
    Maternal and Child Health Journal 11/2010; 16(1):109-18. DOI:10.1007/s10995-010-0712-6 · 2.24 Impact Factor
  • Ralph I. Horwitz
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    ABSTRACT: My path to medicine was unremarkable. My parents loved me. My siblings irritated me. We lived in a working class neighborhood in Philadelphia where factory jobs and union membership were the common currency of everyday life. For immigrant parents with hopes of a better life for their children, there was only one path: success at school and a life in law or medicine. My brother chose law. I chose medicine.
    Medicine Science and Dreams, 10/2010: pages 303-312;
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    R A Marrie · R I Horwitz · G Cutter · T Tyry · T Vollmer
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    ABSTRACT: Comorbidity may be associated with the clinical phenotype of disease and may affect prognostication and treatment decisions. Using the North American Research Committee on Multiple Sclerosis Registry, we described comorbidities present at onset and diagnosis of multiple sclerosis (MS) and examined whether comorbidities present at onset were associated with clinical course or age of MS symptom onset. In 2006, 8983 participants reported their physical and mental comorbidities; smoking status; height; and past and present weight. We compared clinical course at onset and age of symptom onset by comorbidity status. At MS onset, a substantial proportion of participants had physical (24%) or mental (8.4%) comorbidities. The mean (SD) age of MS onset was 31.2 (9.0) years. Vascular, autoimmune, cancer, visual, and musculoskeletal comorbidities were associated with a later age of symptom onset. Among men and women, the odds of a relapsing course at onset were increased if mental comorbidities (OR 1.48; 1.08-2.01) were present at symptom onset. In women, gastrointestinal comorbidities (OR 1.78; 1.25-2.52) and obesity (OR 2.08 1.53-2.82) at MS onset were also associated with a relapsing course at onset. Comorbidity is frequently present at onset of MS and is associated with differences in clinical characteristics.
    Acta Neurologica Scandinavica 09/2010; 124(2):135-41. DOI:10.1111/j.1600-0404.2010.01436.x · 2.40 Impact Factor
  • Ruth Ann Marrie · Ralph I Horwitz
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    ABSTRACT: Although the interaction between comorbidities and chronic diseases is strong, the effect of comorbidities receives little attention in many chronic diseases. In multiple sclerosis (MS), an increasing amount of evidence suggests that physical and mental comorbidities, and adverse health factors such as smoking and obesity, are common and can affect the disease. These comorbid diseases and lifestyle factors affect clinical phenotype, the diagnostic delay between symptom onset and diagnosis, disability progression, and health-related quality of life. Future studies of comorbidity and MS should consider comorbidities and health behaviours and should take into account the modifying effects of socioeconomic status, ethnic origin, and cultural factors. Studies of the frequency of comorbidities in patients with MS should be population based, incorporating appropriate comparator groups. These studies should expand the range of comorbidities assessed, and examine how the frequency of comorbidities is changing over time. Further research is needed to answer many other questions about comorbidities and their associations with MS, including the best way to measure and analyse comorbidities to understand these associations.
    The Lancet Neurology 08/2010; 9(8):820-8. DOI:10.1016/S1474-4422(10)70135-6 · 21.90 Impact Factor
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    RA Marrie · R Rudick · R Horwitz · G Cutter · T Tyry · D Campagnolo · T Vollmer
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    ABSTRACT: Vascular comorbidity adversely influences health outcomes in several chronic conditions. Vascular comorbidities are common in multiple sclerosis (MS), but their impact on disease severity is unknown. Vascular comorbidities may contribute to the poorly understood heterogeneity in MS disease severity. Treatment of vascular comorbidities may represent an avenue for treating MS. A total of 8,983 patients with MS enrolled in the North American Research Committee on Multiple Sclerosis Registry participated in this cohort study. Time from symptom onset or diagnosis until ambulatory disability was compared for patients with or without vascular comorbidities to determine their impact on MS severity. Multivariable proportional hazards models were adjusted for sex, race, age at symptom onset, year of symptom onset, socioeconomic status, and region of residence. Participants reporting one or more vascular comorbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions reported (hazard ratio [HR]/condition for early gait disability 1.51; 95% confidence interval [CI] 1.41-1.61). Vascular comorbidity at any time during the disease course also increased the risk of ambulatory disability (adjusted HR for unilateral walking assistance 1.54; 95% CI 1.44-1.65). The median time between diagnosis and need for ambulatory assistance was 18.8 years in patients without and 12.8 years in patients with vascular comorbidities. Vascular comorbidity, whether present at symptom onset, diagnosis, or later in the disease course, is associated with a substantially increased risk of disability progression in multiple sclerosis. The impact of treating vascular comorbidities on disease progression deserves investigation.
    Neurology 03/2010; 74(13):1041-7. DOI:10.1212/WNL.0b013e3181d6b125 · 8.29 Impact Factor
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    Abraham Verghese · Ralph I Horwitz
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    ABSTRACT: It provides reason and ritual
    BMJ (online) 12/2009; 339(dec16 3):b5448. DOI:10.1136/bmj.b5448 · 17.45 Impact Factor
  • Daniel Jane-wit · Ralph I Horwitz · John Concato
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    ABSTRACT: Randomized controlled trials (RCTs) are considered the highest grade of research evidence, yet properly conducted trials investigating the same association often yield conflicting results. Our objective was to assess whether variability in treatment protocols of RCTs investigating the same topic could explain distinct patterns of outcomes. A review of meta-analyses identified clinical topics involving RCTs with variable pharmacologic dosing and disparate outcomes. Topics were retained if at least two pairs of trials had results suggesting contradictory yet strong exposure-outcome associations. The search yielded 6 clinical topics and 58 RCTs, and individual RCTs were classified into two groups, based on low and high dosages of the intervention. Aggregate odds ratios for studies in the low- and high-dose groups were often substantially discordant. For example, odds ratios were 1.76 (95% confidence interval [CI]=1.02-3.03) for low-dose and 0.56 (95% CI=0.31-1.03) for high-dose trials evaluating low-molecular weight heparin and pulmonary embolism. In an exploratory analysis, outcomes for low- and high-dose groups in the comparison arms of trials (including patients assigned to placebo) had statistically significant differences in four of five analyzable topics, suggesting differences in patient characteristics across trials. Conflicting results from RCTs can represent a spectrum of "real" outcomes for specific treatments. Such trials are best evaluated by considering concurrently both the validity of study design as well as the generalizability of patients and interventions involved.
    Journal of clinical epidemiology 10/2009; 63(1):56-63. DOI:10.1016/j.jclinepi.2009.02.010 · 3.42 Impact Factor
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    Ralph I Horwitz
    The Journal of clinical investigation 10/2009; 119(10):2859-60. DOI:10.1172/JCI41032 · 13.22 Impact Factor

Publication Stats

17k Citations
3,265.49 Total Impact Points


  • 2008–2013
    • Stanford University
      • Department of Medicine
      Palo Alto, California, United States
  • 2011
    • Western Kentucky University
      Боулинг-Грин, Kentucky, United States
  • 1978–2011
    • Yale University
      • • Department of Internal Medicine
      • • School of Medicine
      New Haven, Connecticut, United States
  • 2009
    • Stanford Medicine
      • Department of Medicine
      Stanford, California, United States
  • 2005–2009
    • Case Western Reserve University
      • • Case Comprehensive Cancer Center
      • • School of Medicine
      Cleveland, OH, United States
  • 2004
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 2003
    • University of Michigan
      • Department of Neurology
      Ann Arbor, MI, United States
  • 1986–2003
    • Yale-New Haven Hospital
      • Department of Laboratory Medicine
      New Haven, Connecticut, United States
  • 1999
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 1997
    • Boston Medical Center
      Boston, Massachusetts, United States
    • Boston University
      Boston, Massachusetts, United States
  • 1996
    • University of Washington Seattle
      • Division of General Internal Medicine
      Seattle, WA, United States
  • 1995–1996
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1992–1993
    • McGill University
      Montréal, Quebec, Canada
  • 1988
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1981
    • Harvard Medical School
      • Department of Pathology
      Boston, Massachusetts, United States