EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.

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1 NAME Marcantonio, Edward R. BIOGRAPHICAL SKETCH Provide the following information for the key personnel in the order listed for Form Page 2. Follow the sample format for each person. DO NOT EXCEED FOUR PAGES. era COMMONS USER NAME (credential, e.g., agency login) Marcantonio POSITION TITLE Professor of Medicine EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) INSTITUTION AND LOCATION DEGREE (if applicable) YEAR(s) FIELD OF STUDY Harvard College, Cambridge, MA AB 1983 Biochemical Sciences Harvard Medical School, Boston, MA MD 1987 Medicine Brigham and Women s Hospital, Boston, MA Residency 1990 Internal Medicine Harvard School of Public Health, Boston, MA SM 1992 Epidemiology Harvard Medical School, Boston, MA Fellowship 1992 General Internal Medicine Beth Israel Hospital, Boston, MA Fellowship 1994 Geriatric Medicine A. Personal Statement I serve as Section Chief for Research in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center (BIDMC) and am a Professor of Medicine at Harvard Medical School. I am an internationally recognized expert and clinical investigator in the area of delirium. I have conducted a series of observational and interventional studies designed to improve delirium identification, target individuals at risk, identify modifiable risk factors, and test intervention strategies to reduce the incidence, severity and duration of delirium. I currently lead three NIH-funded studies in delirium research, including the Biomarker Discovery for Delirium project within the first NIH-funded program project in the field of delirium research. I am delighted to serve as the Associate Director of the Research Education Core (REC) of the Boston Older Americans Independence Center (OAIC). Funding from the OAIC has been instrumental in my own career development, and I am happy to be involved in providing similar support to the next generation of promising new scientists in the field of aging. Working closely with the REC Director, Dr. Lewis Lipsitz, with whom I have collaborated for over 20 years, and REC Associate Director Dr. Amy Wagers, I look forward to my involvement in all REC activities. In particular, I will participate in the solicitation of REC proposals, selection of awardees, and in their monitoring and mentoring over the course of their Awards. In addition, I will lead the Advanced Aging Research Training Seminar Series, which will serve as one of the primary required didactic curricula for all REC awardees. I look forward to working with overall OAIC PI Dr. Shallender Bhasin and the rest of the OAIC leadership as we execute our Aims, which will result in the expansion of aging research in the Boston community, thereby positively impacting the independence of older Americans nationwide. Below are representative publications relevant to the OAIC theme of functional promoting therapies in older adults. References b-d also involve the mentorship of junior investigators. a. Marcantonio ER, Flacker JM, Michaels M, Resnick NM. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000;48: b. Givens JL, Sanft TB, Marcantonio ER. Functional recovery after hip fracture: the combined effects of depressive symptoms, cognitive impairment, and delirium. J Am Geriatr Soc 2008;56(6): c. Rudolph JL, Inouye SK, Jones RN, Yang FM, Fong TG, Levkoff SE, Marcantonio ER. Delirium: an independent predictor of functional decline after cardiac surgery. J Am Geriatr Soc 2010;58(4): PMCID: PMC d. Fowler-Brown A, Wee C, Marcantonio E, Ngo L, Leveille S. The Mediating Effect of Chronic Pain on the Relationship between obesity and physical function and disability in older adults. J Am Geriatr Soc. 2013; 61: PMCID: PMC B. Positions and Honors Positions and Employment Instructor in Medicine, Harvard Medical School, Boston, MA Assistant Professor of Medicine, Harvard Medical School, Boston, MA Director of Research, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, MA

2 Associate Professor of Medicine, Harvard Medical School, Boston, MA Director, Aging Research Program, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, MA Section Chief for Research, Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, MA Professor of Medicine, Harvard Medical School, Boston, MA Other Experience and Professional Memberships Member, American College of Physicians Member, Society of General Internal Medicine Member, American Geriatrics Society Member, Gerontological Society of America Director, Harvard National Training Center, Hartford-AFAR Medical Student Scholars Program Editorial Board, Journal of the American Geriatrics Society Research Committee, American Geriatrics Society Aging Systems and Geriatrics Study Section, Center for Scientific Review, National Institutes of Health, Ad hoc member , Empaneled Member , Chair, Distinguished Professor of Geriatrics Committee, Society of General Internal Medicine Editorial Board, Journal of the American Medical Directors Association Council of Mentors, Harvard Medical School Geriatrics Task Force, Society of General Internal Medicine NIA Beeson Career Development Award Review Committee, member Editorial Board, Journal of Gerontology: Medical Sciences 2014 Co-Chair, AGS/NIA U13 Conference on Delirium Research Honors 1983 A.B., Summa cum laude, Harvard College 1997 New Investigator Award, American Geriatrics Society 1999 Paul Beeson Physician Faculty Scholarship for Aging Research 2003 Outstanding Scientific Achievement for Clinical Investigation Award, American Geriatrics Society 2005 Best Doctors in America 2007 Excellence in Mentoring Award, Beth Israel Deaconess Medical Center 2009 A. Clifford Barger Excellence in Mentoring Award, Harvard Medical School 2012 Lumlean Lectureship, Royal College of Physicians, London, United Kingdom 2014 Elected Member, Association of American Physicians C. Contributions to Science 1. Epidemiology of Postoperative Delirium: When I began my career in aging research in the early 1990 s, the epidemiology of delirium was not well described. In the series of studies below, I defined the incidence and risk factors for delirium after elective non-cardiac surgery (a) and cardiac surgery (c). It was also believed that delirium was short-lived and had no impact on long term outcomes. Instead, we found that delirium was an independent risk factor for poor functional recovery after hip fracture (b) and was associated with an acute decline, prolonged recovery, and persistent decline in cognitive function after cardiac surgery (d). I conceived and executed all of these studies, and served as first author or senior author on the resulting manuscripts. a. Marcantonio ER, Goldman L, Mangione CM, Ludwig L, Muraca B, Haslauer CM, Donaldson MC, Whittemore AD, Sugarbaker DJ, Poss R, Haas S, Cook EF, Orav EJ, Lee TH. A clinical prediction rule for delirium after elective non-cardiac surgery. JAMA 1994; 271(2): b. Marcantonio ER, Flacker JM, Michaels M, Resnick NM. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc 2000;48(6): c. Rudolph JL, Jones RN, Levkoff SE, Rockett C, Inouye SK, Sellke FW, Khuri SF, Lipsitz LA, Ramlawi B, Levitsky S, Marcantonio ER. Derivation and validation of a preoperative prediction rule for delirium after cardiac surgery. Circulation 2009;119(2): PMCID: PMC d. Saczynski JS*, Marcantonio ER* (co-first), Quach L, Fong TG, Gross A, Inouye SK, Jones RN (co-last). Cognitive trajectories after postoperative delirium. New Eng J Med. 2012; 367: PMCID: PMC

3 2. Interventions for Delirium: A second major emphasis of my career has been the development and testing of interventions for the prevention or abatement of delirium. I first identified modifiable risk factors for delirium, such as postoperative medications (a). Using these risk factors, I developed a model of proactive geriatrics consultation for hip fracture patients, and tested it in a randomized trial that demonstrated a significant 36% reduction in postoperative delirium and a greater than 50% reduction in the incidence of severe delirium (b). I also developed a program for management of persistent delirium in post-acute skilled nursing facilities, and tested it in cluster randomized trial (c). The program led to a greater than 3-fold improvement in recognition of delirium, but did not result in a shortening of its course. I have also tested novel pharmacological interventions for delirium, including performing a randomized trial of donepezil, a cholinesterase inhibitor commonly used for treatment of dementia (d). While this did not show a benefit, the trial was a valuable contribution to the field in that it led to reduced unnecessary exposure to these drugs in patients at risk for delirium. a. Marcantonio ER, Juarez G, Goldman L, Mangione CM, Ludwig LE, Lind L, Katz N,Cook EF, Orav EJ, Lee TH. The relationship of postoperative delirium with psychoactive medications. JAMA 1994;272(19): b. Marcantonio ER, Flacker JM, Wright JR, Resnick NM. Reducing delirium after hip fracture: a randomized trial. J Am Geriatr Soc 2001;49(5): c. Marcantonio ER, Bergmann MA, Kiely DK, Orav EJ, Jones RN. Randomized trial of a delirium abatement program for post-acute skilled nursing facilities. J Am Geriatr Soc 2010; 58(6): PMCID: PMC d. Marcantonio ER, Palihnich KA, Appleton P, Davis RB. Pilot randomized trial of donepezil hydrochloride for delirium after hip fracture. J Am Geriatr Soc; 2011; 59 Suppl 2: S PMCID: PMC Improved Assessment Methods for Delirium: Delirium can be challenging to assess, both in research and clinical settings. Another major focus of my career has been to develop better measurement tools for delirium. Using a database of nearly 5000 detailed delirium assessments with cognitive testing, we used item response theory, an innovative modern measurement approach, to identify the optimal screening items for delirium (a). We used these data to develop both an improved severity instrument for delirium (the CAM-S) (b), and a brief structured diagnostic interview for delirium that can be completed in 3 minutes or less (the 3D- CAM) (c). The latter 2 tools are already being widely adopted in research. We are now pursuing new work to develop strategies for clinical implementation, including development of an ultra-brief 2-item bedside screening test of delirium (d). Getting both screening questions correct effectively rules out delirium. a. Yang FM, Jones RN, Inouye SK, Tommet D, Crane PK, Rudolph JL, Ngo LH, Marcantonio ER. Selecting optimal screening items for delirium: an application of item response theory. BMC Medical Research Methodology Jan 22;13:8. doi: / PMCID: PMC b. Inouye SK, Kosar CM, Tommet D, Schmitt EM; Puelle MR; Saczynski JS, Marcantonio ER*, Jones RN* (co-last). The CAM-S, a new scoring system for delirium severity in 2 cohorts. Ann Int Med. 2014; 160: PMCID: PMC c. Marcantonio ER, Ngo L, O Connor MA, Jones RN, Crane PK, Metzger ED, Inouye SK. 3D-CAM: Validation of a 3-Minute Diagnostic Interview for CAM-defined Delirium. Ann Int Med. 2014;161(8): PMCID: PMC d. Fick DM, Inouye SK, Guess J, Ngo LH, Jones RN, Saczynski JS, Marcantonio ER. Preliminary development of an ultra-brief 2-item bedside test for delirium. J Hosp Med Oct;10(10): PMCID In Process. 4. Biomarkers and Mechanisms of Delirium: Despite its prevalence, morbidity, and cost, delirium remains a wholly clinical diagnosis and very little is known about its underlying mechanisms. Moreover, there are no biomarkers to guide its diagnosis or management. A relatively recent focus of my career has been to identify blood and cerebrospinal fluid (CSF)-based biomarkers and genetic markers for delirium. We first conducted a systematic review of the state of the field (a). Using serum collected from a cohort of cardiac surgery patients, we identified chemokines, inflammatory markers that may regulate permeability of the blood-brain barrier, as potential blood-based biomarkers of delirium (b). Using a large cohort of non-cardiac surgery patients free of dementia, we found that Apo-E genotype was not associated with delirium (c). Finally, using the same cohort and a matched, nested case-control design, we found that interleukin (IL)-6 at postoperative day 2 and IL-2 were significantly associated with delirium. This is an active area of investigation and I have several more papers under review and in preparation in this general topic area. a. Marcantonio ER, Rudolph JL, Culley D, Crosby G, Alsop D, Inouye SK. Serum biomarkers for delirium. J Gerontol A Biol Sci Med Sci 2006;61(12):

4 b. Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW, Khabbaz K, Levkoff SE, Marcantonio ER. Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci 2008;63(2): PMCID: PMC c. Vasunilashorn S, Ngo L, Kosar CM, Fong TG, Jones RN, Inouye SK,* Marcantonio ER.* (co-last) Does apolipoprotein E genotype increase risk for postoperative delirium? Am J Geriatr Psychiatry Oct;23(10): PMCID In Process. d. Vasunilashorn SM*, Ngo L* (*co-first), Inouye SK, Libermann TA, Jones RN, Alsop DC, Guess J, Jastrzebski S, McElhaney JE, Kuchel GA**, Marcantonio ER** (**co-last). Cytokines and postoperative delirium in older patients undergoing major elective surgery. J Gerontol Med Sci. Epub ahead of print: 2015 July Delirium in Post-acute Care: With progressive shortening of hospital length of stay, and increasingly recognition of the persistence of delirium, I sought out to examine the epidemiology of delirium in post-acute skilled nursing facilities. Using secondary data from the Minimum Dataset, we found that delirium was common in post-acute care, persisted for weeks in this setting, and was associated with poor functional recovery (a). We proceeded to conduct our own primary data collection studies, which confirmed similar findings, and demonstrated that delirium on post-acute admission was a potent risk factor increasing the likelihood of hospital readmission and death, and decreasing the likelihood of return to the community (b). We further found that persistent delirium in the post-acute setting impeded functional recovery (c) and greatly increased the risk of mortality (d), while delirium resolution predicted functional recovery (c) and reduced mortality (d). a. Marcantonio ER, Simon SE, Bergmann MA, Jones RN, Murphy KM, Morris JN. Delirium symptoms in post-acute care: prevalent, persistent, and associated with poor functional recovery. J Am Geriatr Soc 2003;51(1):4-9. b. Marcantonio ER, Kiely DK, Simon SE, Orav EJ, Jones RN, Murphy KM, Bergmann MA. Outcomes of older people admitted to post-acute facilities with delirium. J Am Geriatr Soc 2005;53(6): c. Kiely DK, Jones RN, Bergmann MA, Murphy KM, Orav EJ, Marcantonio ER. Association between delirium resolution and functional recovery among newly admitted post-acute facility patients. J Gerontol A Biol Sci Med Sci 2006;61(2): d. Kiely DK, Marcantonio ER, Inouye SK, Shaffer ML, Bergmann MA, Yang FM, Fearing MA, Jones RN. Persistent delirium predicts greater mortality. J Am Geriatr Soc 2009;57(1): PMCID: PMC Complete List of Published Work in Harvard Catalyst Profiles: D. Research Support. Ongoing Research Support P01 AG (Inouye) 4/15/2010-3/31/2016 Interdisciplinary Study of Delirium and Its Long-Term Outcomes The Program Project entitled Interdisciplinary Study of Mechanisms and Long-Term Outcomes of Delirium seeks to elucidate the correlates of delirium and to examine delirium s contribution to long-term cognitive and functional decline. The project, also known as SAGES: Successful Aging after Elective Surgery, enrolled 566 patients undergoing scheduled non-cardiac surgery at Beth Israel Deaconess Medical Center (BIDMC) and Brigham and Women s Hospital, and 119 BIDMC primary care patients who serve as non-surgical controls. The Epidemiology Core, led by Dr. Marcantonio, played a central role assembling, maintaining, and following this cohort over the follow-up period. Project 2--Biomarker Discovery for Delirium, also led by Dr. Marcantonio, integrated biomarker discovery into the project by collecting blood from the entire surgical cohort at 4 time points and applying two state-of-the-art biomarker discovery techniques, 1) simultaneous assessment of multiple inflammatory cytokines using a multiplex analyzer, and 2) proteomics using quantitative mass spectrometry, in matched samples of surgical patients who developed and did not develop delirium. Role: Project Leader, Core Leader K24 AG (Marcantonio) 9/30/2010-5/31/2016 NIN/National Institute on Aging Mid-Career Mentoring Award for Patient-Oriented Research (POR) in Aging The Specific Aims are: 1. To continue to build a research program around improving the quality and outcomes of care for hospitalized older adults with delirium. This K24 enables me to leverage my currently funded studies

5 and other ongoing work to support the work of trainees, who in turn expand my research program. 2. To build a mentorship program that expands POR in aging at BIDMC and HMS, with a focus on delirium and related conditions. This objective is accomplished through structured, individual mentorship of young investigators with a strong interest in POR. Protected time for mentorship is provided by the K24 award. 3. To expand my mentorship program to include translational, interdisciplinary work around biomarker discovery for delirium, and biomarker applications to improve risk stratification, diagnosis, and prognostication of older adults with delirium. This objective is accomplished through my new research projects, career development activities, and interdisciplinary collaborations that will be facilitated by receipt of the K24 award. Role: Principal Investigator R01 AG (Inouye) 6/15/2014-2/28/2019 Development and Validation of a Delirium Severity Toolkit The goal of this project is to develop a Delirium Severity Toolkit, a dynamic set of six new measures developed with expert clinical judgment and patient/family/nurse input using modern psychometric theory. Our measures will capture the severity of delirium in various phenomenological presentations (e.g., hypoactive, hyperactive), incorporate multiple perspectives (patient, family member, and nurse), will be useful to a broad array of stakeholders (physicians, nurses, patients, family caregivers, researchers, and policy-makers), and will be developed using state-of-the-art procedures that combine qualitative and quantitative approaches such as those developed and utilized in current major NIH-supported measurement initiatives (e.g., PROMIS, NIH Toolbox, Neuro-QOL). Moreover, our development work will be in compliance with FDA guidance on instrument development to assure applicability for future clinical trials. Role: Site PI, Co-Investigator Completed Research Support (selected) R01 HL (Gruber-Baldini) 2/14/2008-1/31/2014 NIH/National Heart Lung and Blood Institute FOCUS Hip Fracture Transfusion Trial: Delirium and Other Cognitive Outcomes This is an ancillary study to a large clinical trial examining different thresholds for blood transfusion to treat blood loss after hip fracture surgery. The ancillary study examined whether transfusion helps prevent shortterm (post-randomization) and long-term (30 day) changes in severity of delirium symptoms. Role: Co-Investigator R21 AG (Xie) 9/1/2011 8/31/2014 Role of Alzheimer s-associated Abeta in POD and POCD The objective of this research was to investigate the role of b-amyloid protein (Ab) and cytokine IL-6 in the neuropathogenesis of post-operative delirium (POD) and post-operative cognitive dysfunction (POCD) in humans. Specifically, we determined whether reduced Aβ levels and elevated IL-6 levels in the pre-operative cerebrospinal fluid (CSF) are associated with higher incidence and greater severity of POD and POCD. Role: Co-Investigator R01 AG (Marcantonio) 9/1/2008-6/30/2015 3D-CAM: Deriving and Validating a 3-minute Diagnostic Assessment for Delirium This project aimed to develop, refine, and validate the 3D-CAM: a 3-minute diagnostic assessment for delirium using the CAM algorithm. Using a dataset of 4744 delirium assessments, we mapped items to key diagnostic domains of delirium and used Item Response Theory to identify a subset of items that maximize the screening efficiency for each of these domains. Using the items identified in Aim 1 and multivariable model selection methods, we developed the 3D-CAM. We prospectively validated and tested the inter-rater reliability of the 3D- CAM in a new cohort of 201 older hospitalized patients. We compared the performance of the 3D-CAM with the CAM-ICU, another brief screening protocol for CAM-defined delirium that does not use verbal responses. The 3D-CAM will be an invaluable tool for diagnosis of delirium in hospitalized older adults. Role: Principal Investigator