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When digital medicine becomes the medicine (1/2)

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서울의대 비전추진위원회에서 2018년 11월 발표한 자료입니다.

Publié dans : Santé & Médecine
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When digital medicine becomes the medicine (1/2)

  1. 1. Professor, SAHIST, Sungkyunkwan University Director, Digital Healthcare Institute Yoon Sup Choi, Ph.D. 디지털 의료가 ‘의료’가 될 때 When Digital Medicine Becomes the Medicine
  2. 2. Disclaimer 저는 위의 회사들과 지분 관계, 자문 등으로 이해 관계가 있음을 밝힙니다. 스타트업 벤처캐피털
  3. 3. “It's in Apple's DNA that technology alone is not enough. 
 It's technology married with liberal arts.”
  4. 4. The Convergence of IT, BT and Medicine
  5. 5. 최윤섭 지음 의료인공지능 표지디자인•최승협 컴퓨터 털 헬 치를 만드는 것을 화두로 기업가, 엔젤투자가, 에반 의 대표적인 전문가로, 활 이 분야를 처음 소개한 장 포항공과대학교에서 컴 동 대학원 시스템생명공 취득하였다. 스탠퍼드대 조교수, KT 종합기술원 컨 구원 연구조교수 등을 거 저널에 10여 편의 논문을 국내 최초로 디지털 헬스 윤섭 디지털 헬스케어 연 국내 유일의 헬스케어 스 어 파트너스’의 공동 창업 스타트업을 의료 전문가 관대학교 디지털헬스학과 뷰노, 직토, 3billion, 서지 소울링, 메디히어, 모바일 자문을 맡아 한국에서도 고 있다. 국내 최초의 디 케어 이노베이션』에 활발 을 연재하고 있다. 저서로 와 『그렇게 나는 스스로 •블로그_ http://www •페이스북_ https://w •이메일_ yoonsup.c 최윤섭 의료 인공지능은 보수적인 의료 시스템을 재편할 혁신을 일으키고 있다. 의료 인공지능의 빠른 발전과 광범위한 영향은 전문화, 세분화되며 발전해 온 현대 의료 전문가들이 이해하기가 어려우며, 어디서부 터 공부해야 할지도 막연하다. 이런 상황에서 의료 인공지능의 개념과 적용, 그리고 의사와의 관계를 쉽 게 풀어내는 이 책은 좋은 길라잡이가 될 것이다. 특히 미래의 주역이 될 의학도와 젊은 의료인에게 유용 한 소개서이다. ━ 서준범, 서울아산병원 영상의학과 교수, 의료영상인공지능사업단장 인공지능이 의료의 패러다임을 크게 바꿀 것이라는 것에 동의하지 않는 사람은 거의 없다. 하지만 인공 지능이 처리해야 할 의료의 난제는 많으며 그 해결 방안도 천차만별이다. 흔히 생각하는 만병통치약 같 은 의료 인공지능은 존재하지 않는다. 이 책은 다양한 의료 인공지능의 개발, 활용 및 가능성을 균형 있 게 분석하고 있다. 인공지능을 도입하려는 의료인, 생소한 의료 영역에 도전할 인공지능 연구자 모두에 게 일독을 권한다. ━ 정지훈, 경희사이버대 미디어커뮤니케이션학과 선임강의교수, 의사 서울의대 기초의학교육을 책임지고 있는 교수의 입장에서, 산업화 이후 변하지 않은 현재의 의학 교육 으로는 격변하는 인공지능 시대에 의대생을 대비시키지 못한다는 한계를 절실히 느낀다. 저와 함께 의 대 인공지능 교육을 개척하고 있는 최윤섭 소장의 전문적 분석과 미래 지향적 안목이 담긴 책이다. 인공 지능이라는 미래를 대비할 의대생과 교수, 그리고 의대 진학을 고민하는 학생과 학부모에게 추천한다. ━ 최형진, 서울대학교 의과대학 해부학교실 교수, 내과 전문의 최근 의료 인공지능의 도입에 대해서 극단적인 시각과 태도가 공존하고 있다. 이 책은 다양한 사례와 깊 은 통찰을 통해 의료 인공지능의 현황과 미래에 대해 균형적인 시각을 제공하여, 인공지능이 의료에 본 격적으로 도입되기 위한 토론의 장을 마련한다. 의료 인공지능이 일상화된 10년 후 돌아보았을 때, 이 책 이 그런 시대를 이끄는 길라잡이 역할을 하였음을 확인할 수 있기를 기대한다. ━ 정규환, 뷰노 CTO 의료 인공지능은 다른 분야 인공지능보다 더 본질적인 이해가 필요하다. 단순히 인간의 일을 대신하는 수준을 넘어 의학의 패러다임을 데이터 기반으로 변화시키기 때문이다. 따라서 인공지능을 균형있게 이 해하고, 어떻게 의사와 환자에게 도움을 줄 수 있을지 깊은 고민이 필요하다. 세계적으로 일어나고 있는 이러한 노력의 결과물을 집대성한 이 책이 반가운 이유다. ━ 백승욱, 루닛 대표 의료 인공지능의 최신 동향뿐만 아니라, 의의와 한계, 전망, 그리고 다양한 생각거리까지 주는 책이다. 논쟁이 되는 여러 이슈에 대해서도 저자는 자신의 시각을 명확한 근거에 기반하여 설득력 있게 제시하 고 있다. 개인적으로는 이 책을 대학원 수업 교재로 활용하려 한다. ━ 신수용, 성균관대학교 디지털헬스학과 교수 최윤섭지음 의료인공지능 값 20,000원 ISBN 979-11-86269-99-2 최초의 책! 계 안팎에서 제기 고 있다. 현재 의 분 커버했다고 자 것인가, 어느 진료 제하고 효용과 안 누가 지는가, 의학 쉬운 언어로 깊이 들이 의료 인공지 적인 용어를 최대 서 다른 곳에서 접 를 접하게 될 것 너무나 빨리 발전 책에서 제시하는 술을 공부하며, 앞 란다. 의사 면허를 취득 저가 도움되면 좋 를 불러일으킬 것 화를 일으킬 수도 슈에 제대로 대응 분은 의학 교육의 예비 의사들은 샌 지능과 함께하는 레이닝 방식도 이 전에 진료실과 수 겠지만, 여러분들 도생하는 수밖에 미래의료학자 최윤섭 박사가 제시하는 의료 인공지능의 현재와 미래 의료 딥러닝과 IBM 왓슨의 현주소 인공지능은 의사를 대체하는가 값 20,000원 ISBN 979-11-86269-99-2 레이닝 방식도 이 전에 진료실과 수 겠지만, 여러분들 도생하는 수밖에 소울링, 메디히어, 모바일 자문을 맡아 한국에서도 고 있다. 국내 최초의 디 케어 이노베이션』에 활발 을 연재하고 있다. 저서로 와 『그렇게 나는 스스로 •블로그_ http://www •페이스북_ https://w •이메일_ yoonsup.c
  6. 6. Inevitable Tsunami of Change
  7. 7. 대한영상의학회 춘계학술대회 2017.6
  8. 8. Vinod Khosla Founder, 1st CEO of Sun Microsystems Partner of KPCB, CEO of KhoslaVentures LegendaryVenture Capitalist in SiliconValley
  9. 9. “Technology will replace 80% of doctors”
  10. 10. https://www.youtube.com/watch?time_continue=70&v=2HMPRXstSvQ “영상의학과 전문의를 양성하는 것을 당장 그만둬야 한다. 5년 안에 딥러닝이 영상의학과 전문의를 능가할 것은 자명하다.” Hinton on Radiology
  11. 11. http://rockhealth.com/2015/01/digital-health-funding-tops-4-1b-2014-year-review/
  12. 12. • "2018년 3Q는 역대 최고로 투자 받기 좋은 시기였다” • 2018년 3Q에서 이미 2017년 투자 규모를 능가 • 모든 라운드에서 더 높은 빈도로, 더 큰 금액이 투자되는 entrepreneurs’ market
  13. 13. 헬스케어넓은 의미의 건강 관리에는 해당되지만, 디지털 기술이 적용되지 않고, 전문 의료 영역도 아닌 것 예) 운동, 영양, 수면 디지털 헬스케어 건강 관리 중에 디지털 기술이 사용되는 것 예) 사물인터넷, 인공지능, 3D 프린터, VR/AR 모바일 헬스케어 디지털 헬스케어 중 모바일 기술이 사용되는 것 예) 스마트폰, 사물인터넷, SNS 개인 유전정보분석 예) 암유전체, 질병위험도, 보인자, 약물 민감도 예) 웰니스, 조상 분석 헬스케어 관련 분야 구성도 (ver 0.3) 의료 질병 예방, 치료, 처방, 관리 등 전문 의료 영역 원격의료 원격진료
  14. 14. EDITORIAL OPEN Digital medicine, on its way to being just plain medicine npj Digital Medicine (2018)1:20175 ; doi:10.1038/ s41746-017-0005-1 There are already nearly 30,000 peer-reviewed English-language scientific journals, producing an estimated 2.5 million articles a year.1 So why another, and why one focused specifically on digital medicine? To answer that question, we need to begin by defining what “digital medicine” means: using digital tools to upgrade the practice of medicine to one that is high-definition and far more individualized. It encompasses our ability to digitize human beings using biosensors that track our complex physiologic systems, but also the means to process the vast data generated via algorithms, cloud computing, and artificial intelligence. It has the potential to democratize medicine, with smartphones as the hub, enabling each individual to generate their own real world data and being far more engaged with their health. Add to this new imaging tools, mobile device laboratory capabilities, end-to-end digital clinical trials, telemedicine, and one can see there is a remarkable array of transformative technology which lays the groundwork for a new form of healthcare. As is obvious by its definition, the far-reaching scope of digital medicine straddles many and widely varied expertise. Computer scientists, healthcare providers, engineers, behavioral scientists, ethicists, clinical researchers, and epidemiologists are just some of the backgrounds necessary to move the field forward. But to truly accelerate the development of digital medicine solutions in health requires the collaborative and thoughtful interaction between individuals from several, if not most of these specialties. That is the primary goal of npj Digital Medicine: to serve as a cross-cutting resource for everyone interested in this area, fostering collabora- tions and accelerating its advancement. Current systems of healthcare face multiple insurmountable challenges. Patients are not receiving the kind of care they want and need, caregivers are dissatisfied with their role, and in most countries, especially the United States, the cost of care is unsustainable. We are confident that the development of new systems of care that take full advantage of the many capabilities that digital innovations bring can address all of these major issues. Researchers too, can take advantage of these leading-edge technologies as they enable clinical research to break free of the confines of the academic medical center and be brought into the real world of participants’ lives. The continuous capture of multiple interconnected streams of data will allow for a much deeper refinement of our understanding and definition of most pheno- types, with the discovery of novel signals in these enormous data sets made possible only through the use of machine learning. Our enthusiasm for the future of digital medicine is tempered by the recognition that presently too much of the publicized work in this field is characterized by irrational exuberance and excessive hype. Many technologies have yet to be formally studied in a clinical setting, and for those that have, too many began and ended with an under-powered pilot program. In addition, there are more than a few examples of digital “snake oil” with substantial uptake prior to their eventual discrediting.2 Both of these practices are barriers to advancing the field of digital medicine. Our vision for npj Digital Medicine is to provide a reliable, evidence-based forum for all clinicians, researchers, and even patients, curious about how digital technologies can transform every aspect of health management and care. Being open source, as all medical research should be, allows for the broadest possible dissemination, which we will strongly encourage, including through advocating for the publication of preprints And finally, quite paradoxically, we hope that npj Digital Medicine is so successful that in the coming years there will no longer be a need for this journal, or any journal specifically focused on digital medicine. Because if we are able to meet our primary goal of accelerating the advancement of digital medicine, then soon, we will just be calling it medicine. And there are already several excellent journals for that. ACKNOWLEDGEMENTS Supported by the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences grant UL1TR001114 and a grant from the Qualcomm Foundation. ADDITIONAL INFORMATION Competing interests:The authors declare no competing financial interests. Publisher's note:Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Change history:The original version of this Article had an incorrect Article number of 5 and an incorrect Publication year of 2017. These errors have now been corrected in the PDF and HTML versions of the Article. Steven R. Steinhubl1 and Eric J. Topol1 1 Scripps Translational Science Institute, 3344 North Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA Correspondence: Steven R. Steinhubl (steinhub@scripps.edu) or Eric J. Topol (etopol@scripps.edu) REFERENCES 1. Ware, M. & Mabe, M. The STM report: an overview of scientific and scholarly journal publishing 2015 [updated March]. http://digitalcommons.unl.edu/scholcom/92017 (2015). 2. Plante, T. B., Urrea, B. & MacFarlane, Z. T. et al. Validation of the instant blood pressure smartphone App. JAMA Intern. Med. 176, 700–702 (2016). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. © The Author(s) 2018 Received: 19 October 2017 Accepted: 25 October 2017 www.nature.com/npjdigitalmed Published in partnership with the Scripps Translational Science Institute 디지털 의료의 미래는? 일상적인 의료가 되는 것
  15. 15. 디지털 의료가 ‘의료’가 될 때 •데이터, 데이터, 데이터 •의료 인공지능 •원격 의료 •VR/AR 기반 수련/수술 •디지털 신약 •환자 주도의 의료
  16. 16. What is most important factor in digital medicine?
  17. 17. “Data! Data! Data!” he cried.“I can’t make bricks without clay!” - Sherlock Holmes,“The Adventure of the Copper Beeches”
  18. 18. 데이터, 데이터, 데이터 미래 의료의 근간
  19. 19. 새로운 데이터가 새로운 방식으로 새로운 주체에 의해 측정, 저장, 통합, 분석된다. 데이터의 종류 데이터의 질 데이터의 양 웨어러블 기기 스마트폰 유전 정보 분석 인공지능 SNS 사용자/환자 대중
  20. 20. 디지털 헬스케어의 3단계 •Step 1. 데이터의 측정 •Step 2. 데이터의 통합 •Step 3. 데이터의 분석
  21. 21. Sci Transl Med 2015
  22. 22. 데이터 소스 (1) 스마트폰
  23. 23. 검이경 더마토스코프 안과질환 피부암 기생충 호흡기 심전도 수면 식단 활동량 발열 생리/임신
  24. 24. 데이터 소스 (2) 웨어러블
  25. 25. n n- ng n es h- n ne ne ct d n- at s- or e, ts n a- gs d ch Nat Biotech 2015
  26. 26. http://www.rolls-royce.com/about/our-technology/enabling-technologies/engine-health-management.aspx#sense 250 sensors to monitor the “health” of the GE turbines
  27. 27. Fig 1. What can consumer wearables do? Heart rate can be measured with an oximeter built into a ring [3], muscle activity with an electromyographi sensor embedded into clothing [4], stress with an electodermal sensor incorporated into a wristband [5], and physical activity or sleep patterns via an accelerometer in a watch [6,7]. In addition, a female’s most fertile period can be identified with detailed body temperature tracking [8], while levels of me attention can be monitored with a small number of non-gelled electroencephalogram (EEG) electrodes [9]. Levels of social interaction (also known to a PLOS Medicine 2016
  28. 28. Hype or Hope? Source: Gartner
  29. 29. 데이터 소스 (3) 유전정보
  30. 30. 가타카 (1997)
  31. 31. 가타카 (1997)
  32. 32. 2003 Human Genome Project 13 years (676 weeks) $2,700,000,000 2007 Dr. CraigVenter’s genome 4 years (208 weeks) $100,000,000 2008 Dr. James Watson’s genome 4 months (16 weeks) $1,000,000 2009 (Nature Biotechnology) 4 weeks $48,000 2013 1-2 weeks ~$5,000
  33. 33. The $1000 Genome is Already Here!
  34. 34. •2017년 1월 NovaSeq 5000, 6000 발표 •몇년 내로 $100로 WES 를 실현하겠다고 공언 •2일에 60명의 WES 가능 (한 명당 한 시간 이하)
  35. 35. 2007-11 2011-06 2011-10 2012-04 2012-10 2013-04 2013-06 2013-09 2013-12 2014-10 2015-02 2015-06 2016-02 2017-04 2017-11 2018-04 1,200,000 1,000,000 900,000 650,000 500,000 400,000 300,000 2,000,000 0 3,000,000 5,000,000 100,000 Customer growth of 23andMe
  36. 36. Human genomes are being sequenced at an ever-increasing rate. The 1000 Genomes Project has aggregated hundreds of genomes; The Cancer Genome Atlas (TGCA) has gathered several thousand; and the Exome Aggregation Consortium (ExAC) has sequenced more than 60,000 exomes. Dotted lines show three possible future growth curves. DNA SEQUENCING SOARS 2001 2005 2010 2015 2020 2025 100 103 106 109 Human Genome Project Cumulativenumberofhumangenomes 1000 Genomes TCGA ExAC Current amount 1st personal genome Recorded growth Projection Double every 7 months (historical growth rate) Double every 12 months (Illumina estimate) Double every 18 months (Moore's law) Michael Einsetein, Nature, 2015
  37. 37. more rapid and accurate approaches to infectious diseases. The driver mutations and key biologic unde Sequencing Applications in Medicine from Prewomb to Tomb Cell. 2014 Mar 27; 157(1): 241–253.
  38. 38. 데이터 소스 (4) 디지털 표현형
  39. 39. Digital Phenotype: Your smartphone knows if you are depressed Ginger.io
  40. 40. Digital Phenotype: Your smartphone knows if you are depressed J Med Internet Res. 2015 Jul 15;17(7):e175. The correlation analysis between the features and the PHQ-9 scores revealed that 6 of the 10 features were significantly correlated to the scores: • strong correlation: circadian movement, normalized entropy, location variance • correlation: phone usage features, usage duration and usage frequency
  41. 41. the manifestations of disease by providing a more comprehensive and nuanced view of the experience of illness. Through the lens of the digital phenotype, an individual’s interaction The digital phenotype Sachin H Jain, Brian W Powers, Jared B Hawkins & John S Brownstein In the coming years, patient phenotypes captured to enhance health and wellness will extend to human interactions with digital technology. In 1982, the evolutionary biologist Richard Dawkins introduced the concept of the “extended phenotype”1, the idea that pheno- types should not be limited just to biological processes, such as protein biosynthesis or tissue growth, but extended to include all effects that a gene has on its environment inside or outside ofthebodyoftheindividualorganism.Dawkins stressed that many delineations of phenotypes are arbitrary. Animals and humans can modify their environments, and these modifications andassociatedbehaviorsareexpressionsofone’s genome and, thus, part of their extended phe- notype. In the animal kingdom, he cites damn buildingbybeaversasanexampleofthebeaver’s extended phenotype1. Aspersonaltechnologybecomesincreasingly embedded in human lives, we think there is an important extension of Dawkins’s theory—the notion of a ‘digital phenotype’. Can aspects of ourinterfacewithtechnologybesomehowdiag- nosticand/orprognosticforcertainconditions? Can one’s clinical data be linked and analyzed together with online activity and behavior data to create a unified, nuanced view of human dis- ease?Here,wedescribetheconceptofthedigital phenotype. Although several disparate studies have touched on this notion, the framework for medicine has yet to be described. We attempt to define digital phenotype and further describe the opportunities and challenges in incorporat- ing these data into healthcare. Jan. 2013 0.000 0.002 0.004 Density 0.006 July 2013 Jan. 2014 July 2014 User 1 User 2 User 3 User 4 User 5 User 6 User 7 Date Figure 1 Timeline of insomnia-related tweets from representative individuals. Density distributions (probability density functions) are shown for seven individual users over a two-year period. Density on the y axis highlights periods of relative activity for each user. A representative tweet from each user is shown as an example. npg©2015NatureAmerica,Inc.Allrightsreserved. http://www.nature.com/nbt/journal/v33/n5/full/nbt.3223.html
  42. 42. ers, Jared B Hawkins & John S Brownstein phenotypes captured to enhance health and wellness will extend to human interactions with st Richard pt of the hat pheno- biological sis or tissue effects that or outside m.Dawkins phenotypes can modify difications onsofone’s ended phe- cites damn hebeaver’s ncreasingly there is an heory—the aspects of ehowdiag- Jan. 2013 0.000 0.002 0.004 Density 0.006 July 2013 Jan. 2014 July 2014 User 1 User 2 User 3 User 4 User 5 User 6 User 7 Date Figure 1 Timeline of insomnia-related tweets from representative individuals. Density distributions (probability density functions) are shown for seven individual users over a two-year period. Density on the y axis highlights periods of relative activity for each user. A representative tweet from each user is Your twitter knows if you cannot sleep Timeline of insomnia-related tweets from representative individuals. Nat. Biotech. 2015
  43. 43. Reece & Danforth, “Instagram photos reveal predictive markers of depression” (2016) higher Hue (bluer) lower Saturation (grayer) lower Brightness (darker)
  44. 44. Digital Phenotype: Your Instagram knows if you are depressed Rao (MVR) (24) .     Results  Both All­data and Pre­diagnosis models were decisively superior to a null model . All­data predictors were significant with 99% probability.57.5;(KAll  = 1 K 49.8)  Pre = 1  7 Pre­diagnosis and All­data confidence levels were largely identical, with two exceptions:  Pre­diagnosis Brightness decreased to 90% confidence, and Pre­diagnosis posting frequency  dropped to 30% confidence, suggesting a null predictive value in the latter case.   Increased hue, along with decreased brightness and saturation, predicted depression. This  means that photos posted by depressed individuals tended to be bluer, darker, and grayer (see  Fig. 2). The more comments Instagram posts received, the more likely they were posted by  depressed participants, but the opposite was true for likes received. In the All­data model, higher  posting frequency was also associated with depression. Depressed participants were more likely  to post photos with faces, but had a lower average face count per photograph than healthy  participants. Finally, depressed participants were less likely to apply Instagram filters to their  posted photos.     Fig. 2. Magnitude and direction of regression coefficients in All­data (N=24,713) and Pre­diagnosis (N=18,513)  models. X­axis values represent the adjustment in odds of an observation belonging to depressed individuals, per  Reece & Danforth, “Instagram photos reveal predictive markers of depression” (2016)     Fig. 1. Comparison of HSV values. Right photograph has higher Hue (bluer), lower Saturation (grayer), and lower  Brightness (darker) than left photograph. Instagram photos posted by depressed individuals had HSV values  shifted towards those in the right photograph, compared with photos posted by healthy individuals.    Units of observation  In determining the best time span for this analysis, we encountered a difficult question:  When and for how long does depression occur? A diagnosis of depression does not indicate the  persistence of a depressive state for every moment of every day, and to conduct analysis using an  individual’s entire posting history as a single unit of observation is therefore rather specious. At  the other extreme, to take each individual photograph as units of observation runs the risk of  being too granular. DeChoudhury et al. (5) looked at all of a given user’s posts in a single day,  and aggregated those data into per­person, per­day units of observation. We adopted this  precedent of “user­days” as a unit of analysis .  5   Statistical framework  We used Bayesian logistic regression with uninformative priors to determine the strength  of individual predictors. Two separate models were trained. The All­data model used all  collected data to address Hypothesis 1. The Pre­diagnosis model used all data collected from  higher Hue (bluer) lower Saturation (grayer) lower Brightness (darker)
  45. 45. Digital Phenotype: Your Instagram knows if you are depressed Reece & Danforth, “Instagram photos reveal predictive markers of depression” (2016) . In particular, depressedχ2 07.84, p .17e 64;( All  = 9   = 9 − 1 13.80, p .87e 44)χ2Pre  = 8   = 2 − 1   participants were less likely than healthy participants to use any filters at all. When depressed  participants did employ filters, they most disproportionately favored the “Inkwell” filter, which  converts color photographs to black­and­white images. Conversely, healthy participants most  disproportionately favored the Valencia filter, which lightens the tint of photos. Examples of  filtered photographs are provided in SI Appendix VIII.     Fig. 3. Instagram filter usage among depressed and healthy participants. Bars indicate difference between observed  and expected usage frequencies, based on a Chi­squared analysis of independence. Blue bars indicate  disproportionate use of a filter by depressed compared to healthy participants, orange bars indicate the reverse. 
  46. 46. Digital Phenotype: Your Instagram knows if you are depressed Reece & Danforth, “Instagram photos reveal predictive markers of depression” (2016)   VIII. Instagram filter examples    Fig. S8. Examples of Inkwell and Valencia Instagram filters.  Inkwell converts  color photos to black­and­white, Valencia lightens tint.  Depressed participants  most favored Inkwell compared to healthy participants, Healthy participants 
  47. 47. 데이터 소스 (5) 마이크로바이옴
  48. 48. Leading Edge Review Individualized Medicine from Prewomb to Tomb Eric J. Topol1 ,* 1The Scripps Translational Science Institute, The Scripps Research Institute and Scripps Health, La Jolla, CA 92037, USA *Correspondence: etopol@scripps.edu http://dx.doi.org/10.1016/j.cell.2014.02.012 That each of us is truly biologically unique, extending to even monozygotic, ‘‘identical’’ twins, is not fully appreciated. Now that it is possible to perform a comprehensive ‘‘omic’’ assessment of an individual, including one’s DNA and RNA sequence and at least some characterization of one’s proteome, metabolome, microbiome, autoantibodies, and epigenome, it has become abundantly clear that each of us has truly one-of-a-kind biological content. Well beyond the allure of the match- less fingerprint or snowflake concept, these singular, individual data and information set up a remarkable and unprecedented opportunity to improve medical treatment and develop preventive strategies to preserve health. From Digital to Biological to Individualized Medicine In 2010, Eric Schmidt of Google said ‘‘The power of individual targeting—the technology will be so good it will be very hard for people to watch or consume something that has not in some sense been tailored for them’’ (Jenkins, 2010). Although referring to the capability of digital technology, we have now reached a time of convergence of the digital and biologic do- mains. It has been well established that 0 and 1 are interchange- able with A, C, T, and G in books and Shakespeare sonnets and that DNA may represent the ultimate data storage system (Church et al., 2012; Goldman et al., 2013b). Biological transis- tors, also known as genetic logic gates, have now been devel- oped that make a computer from a living cell (Bonnet et al., 2013). The convergence of biology and technology was further captured by one of the protagonists of the digital era, Steve Jobs, who said ‘‘I think the biggest innovations of the 21st cen- tury will be at the intersection of biology and technology. A new era is beginning’’ (Issacson, 2011). With whole-genome DNA sequencing and a variety of omic technologies to define aspects of each individual’s biology at many different levels, we have indeed embarked on a new era of medicine. The term ‘‘personalized medicine’’ has been used for many years but has engendered considerable confusion. A recent survey indicated that only 4% of the public understand what the term is intended to mean (Stanton, 2013), and the hack- neyed, commercial use of ‘‘personalized’’ makes many people think that this refers to a concierge service of medical care. Whereas ‘‘person’’ refers to a human being, ‘‘personalized’’ can mean anything from having monogrammed stationary or luggage to ascribing personal qualities. Therefore, it was not surprising that a committee representing the National Academy of Sciences proposed using the term ‘‘precision medicine’’ as defined by ‘‘tailoring of medical treatment to the individual char- acteristics of each patient’’ (National Research Council, 2011). Although the term ‘‘precision’’ denotes the objective of exact- ness, ironically, it too can be viewed as ambiguous in this context because it does not capture the sense that the information is derived from the individual. For example, many laboratory tests could be made more precise by assay methodology, and treat- ments could be made more precise by avoiding side effects— without having anything to do with a specific individual. Other terms that have been suggested include genomic, digital, and stratified medicine, but all of these have a similar problem or appear to be too narrowly focused. The definition of individual is a single human being, derived from the Latin word individu, or indivisible. I propose individual- ized medicine as the preferred term because it has a useful double entendre. It relates not only to medicine that is particular- ized to a human being but also the future impact of digital technology on individuals driving their health care. There will increasingly be the flow of one’s biologic data and relevant medical information directly to the individual. Be it a genome sequence on a tablet or the results of a biosensor for blood pres- sure or another physiologic metric displayed on a smartphone, the digital convergence with biology will definitively anchor the individual as a source of salient data, the conduit of information flow, and a—if not the—principal driver of medicine in the future. The Human GIS Perhaps the most commonly used geographic information systems (GIS) are Google maps, which provide a layered approach to data visualization, such as viewing a location via satellite overlaid with street names, landmarks, and real-time traffic data. This GIS exemplifies the concept of gathering and transforming large bodies of data to provide exquisite temporal and location information. With the multiple virtual views, it gives one the sense of physically being on site. Although Google has digitized and thus created a GIS for the Earth, it is now possible to digitize a human being. As shown in Figure 1, there are multi- ple layers of data that can now be obtained for any individual. This includes data from biosensors, scanners, electronic medi- cal records, social media, and the various omics that include Cell 157, March 27, 2014 ª2014 Elsevier Inc. 241
  49. 49. Leading Edge Review Individualized Medicine from Prewomb to Tomb Eric J. Topol1 ,* 1The Scripps Translational Science Institute, The Scripps Research Institute and Scripps Health, La Jolla, CA 92037, USA *Correspondence: etopol@scripps.edu http://dx.doi.org/10.1016/j.cell.2014.02.012 That each of us is truly biologically unique, extending to even monozygotic, ‘‘identical’’ twins, is not fully appreciated. Now that it is possible to perform a comprehensive ‘‘omic’’ assessment of an individual, including one’s DNA and RNA sequence and at least some characterization of one’s proteome, metabolome, microbiome, autoantibodies, and epigenome, it has become abundantly clear that each of us has truly one-of-a-kind biological content. Well beyond the allure of the match- less fingerprint or snowflake concept, these singular, individual data and information set up a remarkable and unprecedented opportunity to improve medical treatment and develop preventive strategies to preserve health. From Digital to Biological to Individualized Medicine In 2010, Eric Schmidt of Google said ‘‘The power of individual targeting—the technology will be so good it will be very hard for people to watch or consume something that has not in some sense been tailored for them’’ (Jenkins, 2010). Although referring to the capability of digital technology, we have now reached a time of convergence of the digital and biologic do- mains. It has been well established that 0 and 1 are interchange- able with A, C, T, and G in books and Shakespeare sonnets and that DNA may represent the ultimate data storage system (Church et al., 2012; Goldman et al., 2013b). Biological transis- tors, also known as genetic logic gates, have now been devel- oped that make a computer from a living cell (Bonnet et al., 2013). The convergence of biology and technology was further captured by one of the protagonists of the digital era, Steve Jobs, who said ‘‘I think the biggest innovations of the 21st cen- tury will be at the intersection of biology and technology. A new era is beginning’’ (Issacson, 2011). With whole-genome DNA sequencing and a variety of omic technologies to define aspects of each individual’s biology at many different levels, we have indeed embarked on a new era of medicine. The term ‘‘personalized medicine’’ has been used for many years but has engendered considerable confusion. A recent survey indicated that only 4% of the public understand what the term is intended to mean (Stanton, 2013), and the hack- neyed, commercial use of ‘‘personalized’’ makes many people think that this refers to a concierge service of medical care. Whereas ‘‘person’’ refers to a human being, ‘‘personalized’’ can mean anything from having monogrammed stationary or luggage to ascribing personal qualities. Therefore, it was not surprising that a committee representing the National Academy of Sciences proposed using the term ‘‘precision medicine’’ as defined by ‘‘tailoring of medical treatment to the individual char- acteristics of each patient’’ (National Research Council, 2011). Although the term ‘‘precision’’ denotes the objective of exact- ness, ironically, it too can be viewed as ambiguous in this context because it does not capture the sense that the information is derived from the individual. For example, many laboratory tests could be made more precise by assay methodology, and treat- ments could be made more precise by avoiding side effects— without having anything to do with a specific individual. Other terms that have been suggested include genomic, digital, and stratified medicine, but all of these have a similar problem or appear to be too narrowly focused. The definition of individual is a single human being, derived from the Latin word individu, or indivisible. I propose individual- ized medicine as the preferred term because it has a useful double entendre. It relates not only to medicine that is particular- ized to a human being but also the future impact of digital technology on individuals driving their health care. There will increasingly be the flow of one’s biologic data and relevant medical information directly to the individual. Be it a genome sequence on a tablet or the results of a biosensor for blood pres- sure or another physiologic metric displayed on a smartphone, the digital convergence with biology will definitively anchor the individual as a source of salient data, the conduit of information flow, and a—if not the—principal driver of medicine in the future. The Human GIS Perhaps the most commonly used geographic information systems (GIS) are Google maps, which provide a layered approach to data visualization, such as viewing a location via satellite overlaid with street names, landmarks, and real-time traffic data. This GIS exemplifies the concept of gathering and transforming large bodies of data to provide exquisite temporal and location information. With the multiple virtual views, it gives one the sense of physically being on site. Although Google has digitized and thus created a GIS for the Earth, it is now possible to digitize a human being. As shown in Figure 1, there are multi- ple layers of data that can now be obtained for any individual. This includes data from biosensors, scanners, electronic medi- cal records, social media, and the various omics that include Cell 157, March 27, 2014 ª2014 Elsevier Inc. 241 countless hours of context to the digit DNA sequence, 2 T transcriptome, and first human GIS ca feat and yielded k individual. But, it ca at this juncture. With drop substantially, automating the anal ogy can readily be providing meaningfu The Omic Tools Whole-Genome an Perhaps the greates domain has been t sequence a human g the pace of Moore’sFigure 1. Geographic Information System of a Human Being
  50. 50. Personalized Medicine & Evidence Based Medicine
  51. 51. 근거 중심 의학에서 근거 수준이 높아질수록 개별 환자보다는 그룹으로 추상화되는 경향
  52. 52. 개별 환자 대신, 환자 집단의 분포로 표현되고 분포 간의 통계적 유의성을 찾는 것이 목적
  53. 53. 모든 가용한 다차원적 데이터를 바탕으로, 개별 환자의 특성에 맞는 치료를 찾을 수 있다면
  54. 54. N-of-One Trial? N-of-One Medicine!
  55. 55. Data-driven Medicine에 대한 두 가지 전략 • top-down: 먼저 가설을 세우고, 그에 맞는 종류의 데이터를 모아서 검증해보자. • bottom-up: 일단 ‘모든’ 데이터를 최대한 많이 모아 놓으면, 뭐라도 큰 게 나오겠지.
  56. 56. • top-down: 먼저 가설을 세우고, 그에 맞는 종류의 데이터를 모아서 검증해보자. • bottom-up: 일단 ‘모든’ 데이터를 최대한 많이 모아 놓으면, 뭐라도 큰 게 나오겠지. Data-driven Medicine에 대한 두 가지 전략
  57. 57. ©2017NatureAmerica,Inc.,partofSpringerNature.Allrightsreserved. NATURE BIOTECHNOLOGY ADVANCE ONLINE PUBLICATION 1 A RT I C L E S In order to understand the basis of wellness and disease, we and others have pursued a global and holistic approach termed ‘systems medicine’1. The defining feature of systems medicine is the collec- tion of diverse longitudinal data for each individual. These data sets can be used to unravel the complexity of human biology and dis- ease by assessing both genetic and environmental determinants of health and their interactions. We refer to such data as personal, dense, dynamic data clouds: personal, because each data cloud is unique to an individual; dense, because of the high number of measurements; and dynamic, because we monitor longitudinally. The convergence of advances in systems medicine, big data analysis, individual meas- urement devices, and consumer-activated social networks has led to a vision of healthcare that is predictive, preventive, personalized, and participatory (P4)2, also known as ‘precision medicine’. Personal, dense, dynamic data clouds are indispensable to realizing this vision3. The US healthcare system invests 97% of its resources on disease care4, with little attention to wellness and disease prevention. Here we investigate scientific wellness, which we define as a quantitative data-informed approach to maintaining and improving health and avoiding disease. Several recent studies have illustrated the utility of multi-omic lon- gitudinal data to look for signs of reversible early disease or disease risk factors in single individuals. The dynamics of human gut and sali- vary microbiota in response to travel abroad and enteric infection was characterized in two individuals using daily stool and saliva samples5. Daily multi-omic data collection from one individual over 14 months identified signatures of respiratory infection and the onset of type 2 diabetes6. Crohn’s disease progression was tracked over many years in one individual using regular blood and stool measurements7. Each of these studies yielded insights into system dynamics even though they had only one or two participants. We report the generation and analysis of personal, dense, dynamic data clouds for 108 individuals over the course of a 9-month study that we call the Pioneer 100 Wellness Project (P100). Our study included whole genome sequences; clinical tests, metabolomes, proteomes, and microbiomes at 3-month intervals; and frequent activity measure- ments (i.e., wearing a Fitbit). This study takes a different approach from previous studies, in that a broad set of assays were carried out less frequently in a (comparatively) large number of people. Furthermore, we identified ‘actionable possibilities’ for each individual to enhance her/his health. Risk factors that we observed in participants’ clinical markers and genetics were used as a starting point to identify action- able possibilities for behavioral coaching. We report the correlations among different data types and identify population-level changes in clinical markers. This project is the pilot for the 100,000 (100K) person wellness project that we proposed in 2014 (ref. 8). An increased scale of personal, dense, dynamic data clouds in future holds the potential to improve our under- standing of scientific wellness and delineate early warning signs for human diseases. RESULTS The P100 study had four objectives. First, establish cost-efficient procedures for generating, storing, and analyzing multiple sources A wellness study of 108 individuals using personal, dense, dynamic data clouds Nathan D Price1,2,6,7, Andrew T Magis2,6, John C Earls2,6, Gustavo Glusman1 , Roie Levy1, Christopher Lausted1, Daniel T McDonald1,5, Ulrike Kusebauch1, Christopher L Moss1, Yong Zhou1, Shizhen Qin1, Robert L Moritz1 , Kristin Brogaard2, Gilbert S Omenn1,3, Jennifer C Lovejoy1,2 & Leroy Hood1,4,7 Personal data for 108 individuals were collected during a 9-month period, including whole genome sequences; clinical tests, metabolomes, proteomes, and microbiomes at three time points; and daily activity tracking. Using all of these data, we generated a correlation network that revealed communities of related analytes associated with physiology and disease. Connectivity within analyte communities enabled the identification of known and candidate biomarkers (e.g., gamma-glutamyltyrosine was densely interconnected with clinical analytes for cardiometabolic disease). We calculated polygenic scores from genome-wide association studies (GWAS) for 127 traits and diseases, and used these to discover molecular correlates of polygenic risk (e.g., genetic risk for inflammatory bowel disease was negatively correlated with plasma cystine). Finally, behavioral coaching informed by personal data helped participants to improve clinical biomarkers. Our results show that measurement of personal data clouds over time can improve our understanding of health and disease, including early transitions to disease states. 1Institute for Systems Biology, Seattle, Washington, USA. 2Arivale, Seattle, Washington, USA. 3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. 4Providence St. Joseph Health, Seattle, Washington, USA. 5Present address: University of California, San Diego, San Diego, California, USA. 6These authors contributed equally to this work. 7These authors jointly supervised this work. Correspondence should be addressed to N.D.P. (nathan.price@systemsbiology.org) or L.H. (lhood@systemsbiology.org). Received 16 October 2016; accepted 11 April 2017; published online 17 July 2017; doi:10.1038/nbt.3870
  58. 58. Leroy Hood, MD, PhD (Institute for Systems Biology)
  59. 59. Pioneer 100 Wellness Project (pilot of 100K person wellness project)
  60. 60. NatureAmerica,Inc.,partofSpringerNature.Allrightsreserved. Intro a b Round 1 Coaching sessions Round 2 Coaching sessions Round 3 Coaching sessions Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7 Month 8 Month 9 Clinical labs Cardiovascular HDL/LDL cholesterol, triglycerides, particle profiles, and other markers Blood sample Metabolomics Xenobiotics and metabolism-related small molecules Blood sample Diabetes risk Fasting glucose, HbA1c, insulin, and other markers Blood sample Inflammation IL-6, IL-8, and other markers Blood sample Nutrition and toxins Ferritin, vitamin D, glutathione, mercury, lead, and other markers Blood sample Genetics Whole genome sequence Blood sample Proteomics Inflammation, cardiovascular, liver, brain, and heart-related proteins Blood sample Gut microbiome 16S rRNA sequencing Stool sample Quantified self Daily activity Activity tracker Stress Four-point cortisol Saliva 모든 가용한 다차원적 데이터를 측정해보자
  61. 61. ©2017NatureAmerica,Inc.,partofSpringerNature.Allrightsreserved. Proteomics Genetic traits Microbiome Coriobacteriia Allergic sensitization GH NEMO CD40L REN T PA HSP 27 LEP SIRT2 IL 6 FABP4 IL 1RA EGF VEGF A CSTB BETA NGF PPBP(2) PPBP NCF2 4E BP1 STAM PB SIRT2 CSF 1IL 6 FGF 21 IL 10RA IL 18R1IL8IL7 TNFSF14 CCL20 FLT3L CXCL10CD5HGFAXIN1 VEGFAOPGDNEROSM APCSINHBCCRP(2)CRPCFHR1HGFAC MBL2 SERPINC1 GC PTGDS ACTA2 ACTA2(2) PDGF SUBUNIT B Deletion Cfhr1 Inflammatory Bowel Disease Activated Partial Thromboplastin Time Bladder Cancer Bilirubin Levels Gamma Linolenic Acid Dihomo gamma Linolenic Acid Arachidonic Acid Linoleic Acid Adrenic Acid Deltaproteobacteria Mollicutes Verrucomicrobiae Coriobacteriales Verrucomicrobiales Verrucomicrobia Coriobacteriaceae 91otu13421 91otu4418 91otu1825 M ogibacteriaceae Unclassified Desulfovibrionaceae Pasteurellaceae Peptostreptococcaceae Christensenellaceae Verrucom icrobiaceae Alanine RatioOm6Om3 AlphaAminoN ButyricAcid Interleukinll6 SmallLdlParticle RatioGlnGln Threonine 3Methylhistidine AverageinflammationScore Mercury DocosapentaenoicAcidDocosatetraenoicAcid EicosadienoicAcidHomalrLeucineOmega3indexTyrosine HdlCholesterolCPeptide 1Methylhistidine 3HydroxyisovalericAcid IsovalerylglycineIsoleucine Figlu TotalCholesterolLinoleicDihomoYLinolejc PalmitoleicAcid ArachidonicAcid LdlParticle ArachidonicEicosapentaenoic Pasteurellales Diversity Tenericutes Clinical labs Metabolomics 5Hydroxyhexanoate Tl16:0(palmiticAcid) Tl18:3n6(gLinolenicAcid)Tl15:0(pentadecanoicAcid)Tl14:1n5(myristoleicAcid)Tl20:2n6(eicosadienoicAcid)Tl20:5n3(eicosapentaenoicAcid) Tl18:2n6(linoleicAcid) Tldm16:0(plasmalogenPalmiticAcid) Tl22:6n3(docosahexaenoicAcid) Tl22:4n6(adrenicAcid) Tl18:1n9(oleicAcid) Tldm18:1n9(plasmalogenOleicAcid) Tl20:4n6(arachidonicAcid) Tl14:0(myristicAcid) Arachidate(20:0) StearoylArachidonoylGlycerophosphoethanolamine(1)* 1Linoleoylglycerophosphocholine(18:2n6) StearoylLinoleoylGlycerophosphoethanolamine(1)* 1Palmitoleoylglycerophosphocholine(16:1)* PalmitoylOleoylGlycerophosphoglycerol(2)* PalmitoylLinoleoylGlycerophosphocholine(1)* Tl20:3n6(diHomoGLinoleicAcid) 2Hydroxypalmitate NervonoylSphingomyelin* Titl(totalTotalLipid) Cholesterol D ocosahexaenoate (dha;22;6n3) Eicosapentaenoate (epa; 20:5n3) 3 Carboxy 4 M ethyl 5 Propyl 2 Furanpropanoate (cm pf) 3 M ethyladipate Cholate Phosphoethanolamine 1 Oleoylglycerol (1 Monoolein) Tigloylglycine Valine sobutyrylglycine soleucine eucine P Cresol Glucuronide* Phenylacetylglutamine P Cresol Sulfate Tyrosine S Methylcysteine Cystine 3 Methylhistidine 1 Methylhistidine N Acetyltryptophan 3 Indoxyl Sulfate Serotonin (5ht) Creatinine Glutamate Cysteine Glutathione Disulfide Gamma Glutamylthreonine*Gamma Glutamylalanine Gamma Glutamylglutamate Gamma Glutamylglutamine Bradykinin, Hydroxy Pro(3) Bradykinin, Des Arg(9) BradykininMannoseBilirubin (e,e)* Biliverdin Bilirubin (z,z) L UrobilinNicotinamide Alpha TocopherolHippurate Cinnam oylglycine Ldl Particle N um ber Triglycerides Bilirubin Direct Alkaline Phosphatase EgfrNon AfrAm erican CholesterolTotal LdlSm all LdlM edium BilirubinTotal Ggt EgfrAfricanAmerican Cystine MargaricAcid ElaidicAcid Proinsulin Hba1c Insulin Triglycerides Ldlcholesterol DihomoGammaLinolenicAcid HsCrp GlutamicAcid Height Weight Leptin BodyMasIndex PhenylaceticAcid Valine TotalOmega3 TotalOmega6 HsCrpRelativeRisk DocosahexaenoicAcid AlphaAminoadipicAcid EicosapentaenoicAcid GammaAminobutyricAcid 5 Acetylam ino 6 Form ylam ino 3 M ethyluracil Adenosine 5 Monophosphate (amp) Gamma Glutamyltyrosine Gamma Glutamyl 2 Aminobutyrate N Acetyl 3 Methylhistidine* 3 Phenylpropionate (hydrocinnamate) Figure 2 Top 100 correlations per pair of data types. Subset of top statistically significant Spearman inter-omic cross-sectional correlations between all data sets collected in our cohort. Each line represents one correlation that was significant after adjustment for multiple hypothesis testing using the method of Benjamini and Hochberg10 at padj < 0.05. The mean of all three time points was used to compute the correlations between analytes. Up to 100 correlations per pair of data types are shown in this figure. See Supplementary Figure 1 and Supplementary Table 2 for the complete inter-omic cross-sectional network. Nature Biotechnology 2017 측정한 모든 종류의 데이터들 중에 가장 correlation이 높은 100개의 pair를 선정
  62. 62. ©2017NatureAmerica,Inc.,partofSpringerNature.Allrightsreserved. A RT I C L E S edges. The majority of edges involved a metabolite (3,309) or a clini- cal laboratory test (3,366), with an additional 20 edges involving the 130 genetic traits tested, 46 with microbiome taxa or diversity score, and 207 with quantified proteins. The inter-omic delta correlation network contained 822 nodes and 2,406 edges. 375 of the edges in the delta correlation network were also present in the cross-sectional network. The cross-sectional correlation network is provided in Supplementary Table 2 (inter-omic only) and Supplementary Table 3 (full). The delta correlation network is provided in Supplementary Table 4 (inter-omic only) and Supplementary Table 5 (full). We identified clusters of related measurements from the cross- sectional inter-omic correlation network using community analysis, an unsupervised (i.e., using unlabeled data to find hidden structure) approach that iteratively prunes the network (removing the edges with the highest betweenness) to reveal densely inter- connected subgraphs (communities)11. Seventy communities of at least two vertices (mean of 10.9 V and 34.9 E) were identi- fied in the cross-sectional inter-omic network at the cutoff with maximum community modularity12 (Supplementary Fig. 2), and are fully visualized as an interactive graph in Cytoscape13 (Supplementary Dataset 1). 70% of the edges in the cross-sec- tional network remained after community edge pruning. The communities often represented a cluster of physiologically related analytes, as described below. Guanidinosuccinate Alanine IsovalerylcarnitineValine NAcetylleucineNAcetylisoleucine2Methylbutyrylcarnitine(c5) IsoleucineLeucine SAdenosylhomocysteine(sah) CysteineCystineMethionineSulfone NAcetyltryptophan NAcetylkynurenine(2) 3IndoxylSulfate Xanthurenate Kynurenine Kynurenate Tryptophan Phenylalanine N Acetylphenylalanine 4Hydroxyphenylpyruvate Phenylpyruvate Tyrosine N Acetyltyrosine Phenylacetylcarnitine G lutam ine G lutam ate N Acetylglycine G lycine Proline N Delta Acetylornithine N Acetylcitrulline Hom oarginine N2,n5 Diacetylornithine Pro Hydroxy Pro 2 Aminoadipate Lysine Deoxycholate Ursodeoxycholate Arachidate (20:0) Nonadecanoate (19:0) Palmitate (16:0) Erucate (22:1n9) Tl16:0 (palmitic Acid) Tl16:1n7 (palmitoleic Acid) Tl18:1n7 (avaccenic Acid) Tl14:1n5 (myristoleic Acid) Tl24:1n9 (nervonic Acid) Tldm18:1n7 (plasmalogen Vaccenic Acid) Tldm18:0 (plasmalogen Stearic Acid) Tl14:0 (myristic Acid) Tl18:2n6 (linoleic Acid) Tldm16:0 (plasmalogen Palmitic Acid) Tl22:1n9 (erucic Acid) Tl20:3n6 (di Homo G Linoleic Acid) Tl20:4n3 (eicosatetranoic Acid) Tl18:1n9 (oleic Acid) Tl18:3n3 (a Linolenic Acid) Tldm18:1n9 (plasmalogen Oleic Acid) 1 Linoleoylglycerophosphocholine (18:2n6) 1 Linolenoylglycerophosphocholine (18:3n3)* 2 Stearoylglycerophosphocholine*1 Palmitoleoylglycerophosphocholine (16:1)*1 Oleoylglycerophosphocholine (18:1)3 Hydroxylaurate2 Hydroxydecanoate3 Hydroxydecanoate 3 Hydroxyoctanoate 2 Hydroxystearate 3 Hydroxysebacate7 Alpha Hydroxy 3 Oxo 4 Cholestenoate (7 Hoca) CholesterolCarnitinePregnanediol 3 Glucuronide Epiandrosterone Sulfate Stearoylcarnitine Myristoleoylcarnitine* Decanoylcarnitine Laurylcarnitine 2 Oleoylglycerol (2 Monoolein) 1 Linolenoylglycerol 1 Palmitoylglycerol (1 Monopalmitin) 1 Linoleoylglycerol (1 Monolinolein) 1 Dihomo Linolenylglycerol (alpha, Gamma) 1 Oleoylglycerol (1 Monoolein) Caprate (10:0) Laurate (12:0) Caprylate (8:0) 5 Dodecenoate (12:1n7) Palm itoyl Sphingom yelin StearoylSphingom yelin Sphinganine NervonoylSphingom yelin* Sphingosine OleoylSphingom yelin 3 Hydroxybutyrate (bhba) Acetoacetate Butyrylcarnitine Propionylcarnitine DihomoLinolenate(20:3n3OrN6) Hexanoylglycine Glycerophosphoethanolamine Tltl(totalTotalLipid) Eicosanodioate Octadecanedioate 3Methyladipate 2MethylmalonylCarnitine PalmitoylEthanolamide NOleoyltaurine N1Methyl2Pyridone5Carboxamide Nicotinamide AlphaTocopherol GammaTocopherol Threonate Oxalate(ethanedioate) Ergothioneine NAcetylalliin Erythritol Cinnamoylglycine SAllylcysteine 2Pyrrolidinone 2Hydroxyisobutyrate Tartronate(hydroxymalonate) 1,3,7Trimethylurate 4Hydroxycoumarin 2AcetamidophenolSulfate 4AcetylphenolSulfate Mannose Erythronate* Pyruvate Lactate Glucose Glycerate Xylitol GammaGlutamylleucine GammaGlutamylphenylalanine Gam m a Glutam ylisoleucine* Gam m a Glutam ylglutam ine Gam m a Glutam ylhistidine G am m a G lutam ylglutam ate Bradykinin,Hydroxy Pro(3) G lycylleucine Succinylcarnitine Succinate Fum arate M alate Alpha Ketoglutarate Citrate Xanthine LDL Particle hs-CRP Relative Risk ProinsulinHba1cInsulin Gamma Linolenic Acid Triglycerides Manganese Dihomo Gamma Linolenic Acid Glutamic AcidLeptin Body Mass Index Total LC Omega9TryptophanLysineVitamin D 5 Hydroxyindoeacetic AcidWeightLactic Acid Linoleic Dihomo Y LinoleioIsovalerylglycineQuinolinic Acid C-PeptideHDL Cholesterol Indoleacetic Acid Adiponectin Phenylalanine Interleukin IL6 Small LDL Particle Ratio Asn Asp HOMA-IR Lignoceric Acid Succinic Acid Homogentisic Acid Homovanillic Acid Average Inflammation Score FIGLU Ratio Gln Gln Magnesium Pyroglutamic Acid Glucose Gondoic Acid Kynurenic Quinolinic Ratio Alpha Amino N Butyric Acid Tyrosine Alanine HDL Large GGT Triglycerides Bilirubin Direct LDL Medium LDL Pattern Alkaline Phosphatase LDL Peak Size Chloride Glucose LDL Particle Num ber LDL Sm all Ferritin CCL19 H G F IL 10RAIL 6 CXCL10 TNFSF14 CCL20CD5 CD40 VEGF A IL18R1OSM CRPF9(2) APCSINHBCCRP(2) MBL2(2)MBL2GC F9 SERPINC1 TPALEPVEGFAVEGFD IL6FABP4CSTBIL1RA Pasteurellales Pasteurellaceae Omega6FattyAcidLevels(DGLA) FG F 21 hs-CRP G am m a G lutam yltyrosine Amino acid metabolism Olink (CVD) Olink (inflammation) Quest diagnostics Genova diagnostics Nucleotides Energy Peptides Carbohydrates Xenobiotics Vitamins and cofactors Lipid metabolism SRM (liver) Metabolites Clinical labs Microbiome Genetic traits Proteins Figure 3 Cardiometabolic community. All vertices and edges of the cardiometabolic community, with lines indicating significant ( adj < 0.05) correlations. Associations with FGF21 (red lines) and gamma-glutamyltyrosine (purple lines) are highlighted. • inter-omics correlation network 의 분석을 통해서 환자들을 몇가지 cluster로 분류 • 가장 큰 cluster (246 Vertices, 1645 Edges): Cardiometaboic Health • four most connected clinical analyses: C-peptide, insulin, HOMA-IR, triglycerides • four most-connected proteins: leptin, C-reactive protein, FGF21, INHBC gamma-glutamyltyrosine FGF21
  63. 63. • inter-omics correlation network 의 분석을 통해서 환자들을 몇가지 cluster로 분류 • 가장 큰 cluster (246 Vertices, 1645 Edges): Cardiometaboic Health • four most connected clinical analyses: C-peptide, insulin, MOMA-IR, triglycerides • four most-connected proteins: leptin, C-reactive protein, FGF21, INHBC atureAmerica,Inc.,partofSpringerNature.Allrightsreserved. A RT I C L E S The largest community (246 V; 1,645 E) contains many clinical analytes associated with cardiometabolic health, such as C-peptide, triglycerides, insulin, homeostatic risk assessment–insulin resistance (HOMA-IR), fasting glucose, high-density lipid (HDL) cholesterol, and small low-density lipid (LDL) particle number (Fig. 3). The four most-connected clinical analytes by degree (the number of edges connecting a particular analyte) were C-peptide (degree 99), insulin (88), HOMA-IR (88), and triglycerides (75). The four most-connected proteins measured using targeted (i.e., selected reaction monitoring analysis) mass spectrometry or Olink proximity extension assays by degree are leptin (18), C-reactive protein (15), fibroblast growth factor 21 (FGF21) (14), and inhibin beta C chain (INHBC) (10). Leptin and C-reactive protein are indicators for cardiovascular risk14,15. FGF21 is positively correlated with the clinical analytes ( = −0.41; padj = 2.1 × 10−3). Hypothyroidism has long been recog- nized clinically as a cause of elevated cholesterol values19. A community formed around plasma serotonin (18 V; 25 E) contain- ing 12 proteins listed in Supplementary Table 6, for which the most significant enrichment identified in a STRING ontology analysis20 was platelet activation (padj = 1.7 × 10−3) (Fig. 4b). Serotonin is known to induce platelet aggregation21; accordingly, selective serotonin reuptake inhibitors (SSRIs) may protect against myocardial infarction22. We identified several communities containing microbiome taxa, suggesting that there are specific microbiome–analyte relationships. Hydrocinnamate, l-urobilin, and 5-hydroxyhexanoate clustered with the bacterial class Mollicutes and family Christensenellaceae (8 V; 8 E). Another community emerged around the Verrucomicrobiaceae and Desulfovibrionaceae families and p-cresol-sulfate (7 V; 6 E). The a c d b e Figure 4 Cholesterol, serotonin, -diversity, IBD, and bladder cancer communities. (a) Cholesterol community. (b) Serotonin community. (c) -diversity community. (d) The polygenic score for inflammatory bowel disease is negatively correlated with cystine. (e) The polygenic score for bladder cancer is positively correlated with 5-acetylamino-6-formylamino-3-methyluracil (AFMU). Cholesterol, serotonin, diversity, IBD, and bladder cancer communities. (a) Cholesterol community. (b) Serotonin community. (c) -diversity community. (d) The polygenic score for inflammatory bowel disease is negatively correlated with cystine. (e) The polygenic score for bladder cancer is positively correlated with 5-acetylamino-6-formylamino-3-methyluracil (AFMU).
  64. 64. 017NatureAmerica,Inc.,partofSpringerNature.Allrightsreserved. identified with elevated fasting glucose or HbA1c at baseline (pre- diabetes), the coach made recommendations based on the Diabetes Prevention Program36, customized for each person’s lifestyle. These individual recommendations typically fell into one of several major factors (fasting insulin and HOMA-IR), and inflammation (IL-8 and TNF-alpha). Lipoprotein fractionation, performed by both labora- tory companies, produced significant but discordant results for LDL particle number. We observed significant improvements in fasting Table 1 Longitudinal analysis of clinical changes by round Clinical laboratory test Changes in labs in participants out-of-range at baseline Health area Name N per round P-value Nutrition Vitamin D 95 +7.2 ng/mL/round 7.1 × 10−25 Nutrition Mercury 81 −0.002 mcg/g/round 8.9 × 10−9 Diabetes HbA1c 52 −0.085%/round 9.2 × 10−6 Cardiovascular LDL particle number (Quest) 30 +130 nmol/L/round 9.3 × 10−5 Nutrition Methylmalonic acid (Genova) 3 −0.49 mmol/mol creatinine/round 2.1 × 10−4 Cardiovascular LDL pattern (A or B) 28 −0.16 /round 4.8 × 10−4 Inflammation Interleukin-8 10 −6.1 pg/mL/round 5.9 × 10−4 Cardiovascular Total cholesterol (Quest) 48 −6.4 mg/dL/round 7.2 × 10−4 Cardiovascular LDL cholesterol 57 −4.8 mg/dL/round 8.8 × 10−4 Cardiovascular LDL particle number (Genova) 70 −69 nmol/L/round 1.2 × 10−3 Cardiovascular Small LDL particle number (Genova) 73 −56 nmol/L/round 3.5 × 10−3 Diabetes Fasting glucose (Quest) 45 −1.9 mg/dL/round 8.2 × 10−3 Cardiovascular Total cholesterol (Genova) 43 −5.4 mg/dL/round 1.2 × 10−2 Diabetes Insulin 16 −2.3 IU/mL/round 1.5 × 10−2 Inflammation TNF-alpha 4 −6.6 pg/mL/round 1.8 × 10−2 Diabetes HOMA-IR 19 −0.56 /round 2.0 × 10−2 Cardiovascular HDL cholesterol 5 +4.5 mg/dL/round 2.2 × 10−2 Nutrition Methylmalonic acid (Quest) 7 −42 nmol/L/round 5.2 × 10−2 Cardiovascular Triglycerides (Genova) 14 −18 mg/dL/round 1.4 × 10−1 Diabetes Fasting glucose (Genova) 47 −0.98 mg/dL/round 1.5 × 10−1 Nutrition Arachidonic acid 35 +0.24 wt%/round 1.9 × 10−1 Inflammation hs-CRP 51 −0.47 mcg/mL/round 2.1 × 10−1 Cardiovascular Triglycerides (Quest) 17 −14 mg/dL/round 2.4 × 10−1 Nutrition Glutathione 6 +11 micromol/L/round 2.5 × 10−1 Nutrition Zinc 4 −0.82 mcg/g/round 3.0 × 10−1 Nutrition Ferritin 10 −14 ng/mL/round 3.1 × 10−1 Inflammation Interleukin-6 4 −1.1 pg/mL/round 3.8 × 10−1 Cardiovascular HDL large particle number 8 +210 nmol/L/round 4.9 × 10−1 Nutrition Copper 10 +0.006 mcg/g/round 6.0 × 10−1 Nutrition Selenium 6 +0.035 mcg/g/round 6.2 × 10−1 Cardiovascular Medium LDL particle number 20 +2.8 nmol/L/round 8.5 × 10−1 Cardiovascular Small LDL particle number (Quest) 14 −2.3 nmol/L/round 8.8 × 10−1 Nutrition Manganese 0 N/A N/A Nutrition EPA 0 N/A N/A Nutrition DHA 0 N/A N/A Generalized estimating equations (GEE) were used to calculate average changes in clinical laboratory tests over time, for those analytes that were actively coached on. The ‘ per round’ column is the average change in the population for that analyte by round adjusted for age, sex, and self-reported ancestry. ‘Out-of-range at baseline’ indicates the average change using only those participants who were out-of-range for that analyte at the beginning of the study. Rows in boldface indicate statistically significant improvement, while the italicized row indicates statistically significant worsening. N/A values are present where no participants were out-of-range at baseline. For example, the average improvement in vitamin D for the 95 participants that began the study out-of-range was +7.2 ng/mL per round. Several analytes are measured by both Quest and Genova; with the exception of LDL particle number, the direction of effect for significantly changed analytes was concordant across the two laboratories. An independence working correlation structure was used in the GEE. See Supplementary Table 10 for the complete results. • 수치가 정상 범위를 벗어나면 코치가 개입하여, 해당 수치를 개선할 수 있는 라이프스타일의 변화 유도 • 예를 들어, 공복혈당 혹은 HbA1c 의 증가: 코치가 당뇨 예방 프로그램(DPP)을 권고 • 몇개의 major category로 나눠짐 • diet, exercise, stress management, dietary supplements, physician referral • 이를 통해서 가장 크게 개선 효과가 있었던 수치들 • vitamin D, mercury, HbA1c • 전반적으로 콜레스테롤 관련 수치나, 당뇨 위험 관련 수치, 염증 수치 등에 개선이 있었음
  65. 65. • 버릴리(구글)의 베이스라인 프로젝트 • 건강과 질병을 새롭게 정의하기 위한 프로젝트 • 4년 동안 만 명의 개인의 건강 상태를 면밀하게 추적하여 데이터를 축적 • 심박수와 수면패턴 및 유전 정보, 감정 상태, 진료기록, 가족력, 소변/타액/혈액 검사 등
  66. 66. • 버릴리(구글)의 베이스라인 프로젝트 • 건강과 질병을 새롭게 정의하기 위한 프로젝트 • 4년 동안 만 명의 개인의 건강 상태를 면밀하게 추적하여 데이터를 축적 • 심박수와 수면패턴 및 유전 정보, 감정 상태, 진료기록, 가족력, 소변/타액/혈액 검사 등
  67. 67. • 버릴리의 ‘Study Watch’ • 2017년 4월 공개한 베이스라인 스터디 용 스마트워치 • 심전도, 심박수, EDA(Electrodermal Activity), 관성움직임(inertial movement) 등 측정 • 장기간 추적연구를 위한 특징들: 배터리 수명(일주일), 데이터 저장 공간, 동기화 (일주일 한 번)
  68. 68. • Linda Avey의 Precise.ly • 23andMe의 공동창업자였던 Linda Avey가 2009년 회사를 떠난 이후, 2011년 창업 • ‘We Are Curious’ 라는 이름에서 최근에 Precise.ly로 회사 이름 변경
  69. 69. • Linda Avey의 Precise.ly • Genotype + Phenotype + Microbiome + environment 모두 결합하여 의학적인 insight • Genotype: Helix의 플랫폼에서 WES 을 통하여 분석 • Phenotype: 웨어러블, IoT 기기를 이용
  70. 70. • ‘Modern diseases’를 주로 타게팅 하겠다고 언급하고 있음 • 예를 들어, autism spectrum syndrome을 다차원적 데이터를 기반으로 분류할 수 있을까? • Helix 플랫폼을 통해서 먼저 Chronic Fatigue 에 대한 앱을 먼저 출시하고, • 향후 autism, PD 등에 대한 앱을 출시할 예정이라고 함.
  71. 71. iCarbonX •중국 BGI의 대표였던 준왕이 창업 •'모든 데이터를 측정'하고 이를 정밀 의료에 활용할 계획 •데이터를 측정할 수 있는 역량을 가진 회사에 투자 및 인수 •SomaLogic, HealthTell, PatientsLikMe •향후 5년 동안 100만명-1000만 명의 데이터 모을 계획 •이 데이터의 분석은 인공지능으로
  72. 72. 현재 Arivale, Baseline Project, Precisely, iCarbon-X 가 모두 잘 되고 있지는 않으나, 이러한 변화의 초창기 시도 정도로 해석 가능
  73. 73. 의료 인공지능 피할 수 없는 미래
  74. 74. 그래서 그 많은 데이터, 어떡할 건데?
  75. 75. 좋은 질문을 던저야, 좋은 답이 나온다
  76. 76. 좋은 질문을 던저야, 좋은 답이 나온다
  77. 77. Martin Duggan,“IBM Watson Health - Integrated Care & the Evolution to Cognitive Computing” 지금 의대생과 전공의는 무엇을 배우나
  78. 78. •복잡한 의료 데이터의 분석 및 insight 도출 •영상 의료/병리 데이터의 분석/판독 •연속 데이터의 모니터링 및 예방/예측 의료 인공지능의 세 유형
  79. 79. •복잡한 의료 데이터의 분석 및 insight 도출 •영상 의료/병리 데이터의 분석/판독 •연속 데이터의 모니터링 및 예방/예측 의료 인공지능의 세 유형
  80. 80. Jeopardy! 2011년 인간 챔피언 두 명 과 퀴즈 대결을 벌여서 압도적인 우승을 차지
  81. 81. ORIGINAL ARTICLE Watson for Oncology and breast cancer treatment recommendations: agreement with an expert multidisciplinary tumor board S. P. Somashekhar1*, M.-J. Sepu´lveda2 , S. Puglielli3 , A. D. Norden3 , E. H. Shortliffe4 , C. Rohit Kumar1 , A. Rauthan1 , N. Arun Kumar1 , P. Patil1 , K. Rhee3 & Y. Ramya1 1 Manipal Comprehensive Cancer Centre, Manipal Hospital, Bangalore, India; 2 IBM Research (Retired), Yorktown Heights; 3 Watson Health, IBM Corporation, Cambridge; 4 Department of Surgical Oncology, College of Health Solutions, Arizona State University, Phoenix, USA *Correspondence to: Prof. Sampige Prasannakumar Somashekhar, Manipal Comprehensive Cancer Centre, Manipal Hospital, Old Airport Road, Bangalore 560017, Karnataka, India. Tel: þ91-9845712012; Fax: þ91-80-2502-3759; E-mail: somashekhar.sp@manipalhospitals.com Background: Breast cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence (AI) clinical decision-support systems (CDSSs) have the potential to help address this challenge. We report here the results of examining the level of agreement (concordance) between treatment recommendations made by the AI CDSS Watson for Oncology (WFO) and a multidisciplinary tumor board for breast cancer. Patients and methods: Treatment recommendations were provided for 638 breast cancers between 2014 and 2016 at the Manipal Comprehensive Cancer Center, Bengaluru, India. WFO provided treatment recommendations for the identical cases in 2016. A blinded second review was carried out by the center’s tumor board in 2016 for all cases in which there was not agreement, to account for treatments and guidelines not available before 2016. Treatment recommendations were considered concordant if the tumor board recommendations were designated ‘recommended’ or ‘for consideration’ by WFO. Results: Treatment concordance between WFO and the multidisciplinary tumor board occurred in 93% of breast cancer cases. Subgroup analysis found that patients with stage I or IV disease were less likely to be concordant than patients with stage II or III disease. Increasing age was found to have a major impact on concordance. Concordance declined significantly (P 0.02; P < 0.001) in all age groups compared with patients <45 years of age, except for the age group 55–64 years. Receptor status was not found to affect concordance. Conclusion: Treatment recommendations made by WFO and the tumor board were highly concordant for breast cancer cases examined. Breast cancer stage and patient age had significant influence on concordance, while receptor status alone did not. This study demonstrates that the AI clinical decision-support system WFO may be a helpful tool for breast cancer treatment decision making, especially at centers where expert breast cancer resources are limited. Key words: Watson for Oncology, artificial intelligence, cognitive clinical decision-support systems, breast cancer, concordance, multidisciplinary tumor board Introduction Oncologists who treat breast cancer are challenged by a large and rapidly expanding knowledge base [1, 2]. As of October 2017, for example, there were 69 FDA-approved drugs for the treatment of breast cancer, not including combination treatment regimens [3]. The growth of massive genetic and clinical databases, along with computing systems to exploit them, will accelerate the speed of breast cancer treatment advances and shorten the cycle time for changes to breast cancer treatment guidelines [4, 5]. In add- ition, these information management challenges in cancer care are occurring in a practice environment where there is little time available for tracking and accessing relevant information at the point of care [6]. For example, a study that surveyed 1117 oncolo- gists reported that on average 4.6 h per week were spent keeping VC The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. Annals of Oncology 29: 418–423, 2018 doi:10.1093/annonc/mdx781 Published online 9 January 2018 Downloaded from https://academic.oup.com/annonc/article-abstract/29/2/418/4781689 by guest WFO는 현재 정확성, 효용성에 대한 근거가 부족하지만, 10년 뒤에도 그러할까?
  82. 82. ORIGINAL ARTICLE Watson for Oncology and breast cancer treatment recommendations: agreement with an expert multidisciplinary tumor board S. P. Somashekhar1*, M.-J. Sepu´lveda2 , S. Puglielli3 , A. D. Norden3 , E. H. Shortliffe4 , C. Rohit Kumar1 , A. Rauthan1 , N. Arun Kumar1 , P. Patil1 , K. Rhee3 & Y. Ramya1 1 Manipal Comprehensive Cancer Centre, Manipal Hospital, Bangalore, India; 2 IBM Research (Retired), Yorktown Heights; 3 Watson Health, IBM Corporation, Cambridge; 4 Department of Surgical Oncology, College of Health Solutions, Arizona State University, Phoenix, USA *Correspondence to: Prof. Sampige Prasannakumar Somashekhar, Manipal Comprehensive Cancer Centre, Manipal Hospital, Old Airport Road, Bangalore 560017, Karnataka, India. Tel: þ91-9845712012; Fax: þ91-80-2502-3759; E-mail: somashekhar.sp@manipalhospitals.com Background: Breast cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence (AI) clinical decision-support systems (CDSSs) have the potential to help address this challenge. We report here the results of examining the level of agreement (concordance) between treatment recommendations made by the AI CDSS Watson for Oncology (WFO) and a multidisciplinary tumor board for breast cancer. Patients and methods: Treatment recommendations were provided for 638 breast cancers between 2014 and 2016 at the Manipal Comprehensive Cancer Center, Bengaluru, India. WFO provided treatment recommendations for the identical cases in 2016. A blinded second review was carried out by the center’s tumor board in 2016 for all cases in which there was not agreement, to account for treatments and guidelines not available before 2016. Treatment recommendations were considered concordant if the tumor board recommendations were designated ‘recommended’ or ‘for consideration’ by WFO. Results: Treatment concordance between WFO and the multidisciplinary tumor board occurred in 93% of breast cancer cases. Subgroup analysis found that patients with stage I or IV disease were less likely to be concordant than patients with stage II or III disease. Increasing age was found to have a major impact on concordance. Concordance declined significantly (P 0.02; P < 0.001) in all age groups compared with patients <45 years of age, except for the age group 55–64 years. Receptor status was not found to affect concordance. Conclusion: Treatment recommendations made by WFO and the tumor board were highly concordant for breast cancer cases examined. Breast cancer stage and patient age had significant influence on concordance, while receptor status alone did not. This study demonstrates that the AI clinical decision-support system WFO may be a helpful tool for breast cancer treatment decision making, especially at centers where expert breast cancer resources are limited. Key words: Watson for Oncology, artificial intelligence, cognitive clinical decision-support systems, breast cancer, concordance, multidisciplinary tumor board Introduction Oncologists who treat breast cancer are challenged by a large and rapidly expanding knowledge base [1, 2]. As of October 2017, for example, there were 69 FDA-approved drugs for the treatment of breast cancer, not including combination treatment regimens [3]. The growth of massive genetic and clinical databases, along with computing systems to exploit them, will accelerate the speed of breast cancer treatment advances and shorten the cycle time for changes to breast cancer treatment guidelines [4, 5]. In add- ition, these information management challenges in cancer care are occurring in a practice environment where there is little time available for tracking and accessing relevant information at the point of care [6]. For example, a study that surveyed 1117 oncolo- gists reported that on average 4.6 h per week were spent keeping VC The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. Annals of Oncology 29: 418–423, 2018 doi:10.1093/annonc/mdx781 Published online 9 January 2018 Downloaded from https://academic.oup.com/annonc/article-abstract/29/2/418/4781689 by guest Table 2. MMDT and WFO recommendations after the initial and blinded second reviews Review of breast cancer cases (N 5 638) Concordant cases, n (%) Non-concordant cases, n (%) Recommended For consideration Total Not recommended Not available Total Initial review (T1MMDT versus T2WFO) 296 (46) 167 (26) 463 (73) 137 (21) 38 (6) 175 (27) Second review (T2MMDT versus T2WFO) 397 (62) 194 (30) 591 (93) 36 (5) 11 (2) 47 (7) T1MMDT, original MMDT recommendation from 2014 to 2016; T2WFO, WFO advisor treatment recommendation in 2016; T2MMDT, MMDT treatment recom- mendation in 2016; MMDT, Manipal multidisciplinary tumor board; WFO, Watson for Oncology. 31% 18% 1% 2% 33% 5% 31% 6% 0% 10% 20% Not available Not recommended RecommendedFor consideration 30% 40% 50% 60% 70% 80% 90% 100% 8% 25% 61% 64% 64% 29% 51% 62% Concordance, 93% Concordance, 80% Concordance, 97% Concordance, 95% Concordance, 86% 2% 2% Overall (n=638) Stage I (n=61) Stage II (n=262) Stage III (n=191) Stage IV (n=124) 5% Figure 1. Treatment concordance between WFO and the MMDT overall and by stage. MMDT, Manipal multidisciplinary tumor board; WFO, Watson for Oncology. 5%Non-metastatic HR(+)HER2/neu(+)Triple(–) Metastatic Non-metastatic Metastatic Non-metastatic Metastatic 10% 1% 2% 1% 5% 20% 20%10% 0% Not applicable Not recommended For consideration Recommended 20% 40% 60% 80% 100% 5% 74% 65% 34% 64% 5% 38% 56% 15% 20% 55% 36% 59% Concordance, 95% Concordance, 75% Concordance, 94% Concordance, 98% Concordance, 94% Concordance, 85% Figure 2. Treatment concordance between WFO and the MMDT by stage and receptor status. HER2/neu, human epidermal growth factor receptor 2; HR, hormone receptor; MMDT, Manipal multidisciplinary tumor board; WFO, Watson for Oncology. Annals of Oncology Original article WFO는 현재 정확성, 효용성에 대한 근거가 부족하지만, 10년 뒤에도 그러할까?
  83. 83. IBM Watson Health Watson for Clinical Trial Matching (CTM) 18 1. According to the National Comprehensive Cancer Network (NCCN) 2. http://csdd.tufts.edu/files/uploads/02_-_jan_15,_2013_-_recruitment-retention.pdf© 2015 International Business Machines Corporation Searching across eligibility criteria of clinical trials is time consuming and labor intensive Current Challenges Fewer than 5% of adult cancer patients participate in clinical trials1 37% of sites fail to meet minimum enrollment targets. 11% of sites fail to enroll a single patient 2 The Watson solution • Uses structured and unstructured patient data to quickly check eligibility across relevant clinical trials • Provides eligible trial considerations ranked by relevance • Increases speed to qualify patients Clinical Investigators (Opportunity) • Trials to Patient: Perform feasibility analysis for a trial • Identify sites with most potential for patient enrollment • Optimize inclusion/exclusion criteria in protocols Faster, more efficient recruitment strategies, better designed protocols Point of Care (Offering) • Patient to Trials: Quickly find the right trial that a patient might be eligible for amongst 100s of open trials available Improve patient care quality, consistency, increased efficiencyIBM Confidential
  84. 84. •“향후 10년 동안 첫번째 cardiovascular event 가 올 것인가” 예측 •전향적 코호트 스터디: 영국 환자 378,256 명 •일상적 의료 데이터를 바탕으로 기계학습으로 질병을 예측하는 첫번째 대규모 스터디 •기존의 ACC/AHA 가이드라인과 4가지 기계학습 알고리즘의 정확도를 비교 •Random forest; Logistic regression; Gradient bossting; Neural network
  85. 85. •2018년 1월 구글이 전자의무기록(EMR)을 분석하여, 환자 치료 결과를 예측하는 인공지능 발표 •환자가 입원 중에 사망할 것인지 •장기간 입원할 것인지 •퇴원 후에 30일 내에 재입원할 것인지 •퇴원 시의 진단명
 •이번 연구의 특징: 확장성 •과거 다른 연구와 달리 EMR의 일부 데이터를 pre-processing 하지 않고, •전체 EMR 를 통채로 모두 분석하였음: UCSF, UCM (시카고 대학병원) •특히, 비정형 데이터인 의사의 진료 노트도 분석
  86. 86. ARTICLE OPEN Scalable and accurate deep learning with electronic health records Alvin Rajkomar 1,2 , Eyal Oren1 , Kai Chen1 , Andrew M. Dai1 , Nissan Hajaj1 , Michaela Hardt1 , Peter J. Liu1 , Xiaobing Liu1 , Jake Marcus1 , Mimi Sun1 , Patrik Sundberg1 , Hector Yee1 , Kun Zhang1 , Yi Zhang1 , Gerardo Flores1 , Gavin E. Duggan1 , Jamie Irvine1 , Quoc Le1 , Kurt Litsch1 , Alexander Mossin1 , Justin Tansuwan1 , De Wang1 , James Wexler1 , Jimbo Wilson1 , Dana Ludwig2 , Samuel L. Volchenboum3 , Katherine Chou1 , Michael Pearson1 , Srinivasan Madabushi1 , Nigam H. Shah4 , Atul J. Butte2 , Michael D. Howell1 , Claire Cui1 , Greg S. Corrado1 and Jeffrey Dean1 Predictive modeling with electronic health record (EHR) data is anticipated to drive personalized medicine and improve healthcare quality. Constructing predictive statistical models typically requires extraction of curated predictor variables from normalized EHR data, a labor-intensive process that discards the vast majority of information in each patient’s record. We propose a representation of patients’ entire raw EHR records based on the Fast Healthcare Interoperability Resources (FHIR) format. We demonstrate that deep learning methods using this representation are capable of accurately predicting multiple medical events from multiple centers without site-specific data harmonization. We validated our approach using de-identified EHR data from two US academic medical centers with 216,221 adult patients hospitalized for at least 24 h. In the sequential format we propose, this volume of EHR data unrolled into a total of 46,864,534,945 data points, including clinical notes. Deep learning models achieved high accuracy for tasks such as predicting: in-hospital mortality (area under the receiver operator curve [AUROC] across sites 0.93–0.94), 30-day unplanned readmission (AUROC 0.75–0.76), prolonged length of stay (AUROC 0.85–0.86), and all of a patient’s final discharge diagnoses (frequency-weighted AUROC 0.90). These models outperformed traditional, clinically-used predictive models in all cases. We believe that this approach can be used to create accurate and scalable predictions for a variety of clinical scenarios. In a case study of a particular prediction, we demonstrate that neural networks can be used to identify relevant information from the patient’s chart. npj Digital Medicine (2018)1:18 ; doi:10.1038/s41746-018-0029-1 INTRODUCTION The promise of digital medicine stems in part from the hope that, by digitizing health data, we might more easily leverage computer information systems to understand and improve care. In fact, routinely collected patient healthcare data are now approaching the genomic scale in volume and complexity.1 Unfortunately, most of this information is not yet used in the sorts of predictive statistical models clinicians might use to improve care delivery. It is widely suspected that use of such efforts, if successful, could provide major benefits not only for patient safety and quality but also in reducing healthcare costs.2–6 In spite of the richness and potential of available data, scaling the development of predictive models is difficult because, for traditional predictive modeling techniques, each outcome to be predicted requires the creation of a custom dataset with specific variables.7 It is widely held that 80% of the effort in an analytic model is preprocessing, merging, customizing, and cleaning nurses, and other providers are included. Traditional modeling approaches have dealt with this complexity simply by choosing a very limited number of commonly collected variables to consider.7 This is problematic because the resulting models may produce imprecise predictions: false-positive predictions can overwhelm physicians, nurses, and other providers with false alarms and concomitant alert fatigue,10 which the Joint Commission identified as a national patient safety priority in 2014.11 False-negative predictions can miss significant numbers of clinically important events, leading to poor clinical outcomes.11,12 Incorporating the entire EHR, including clinicians’ free-text notes, offers some hope of overcoming these shortcomings but is unwieldy for most predictive modeling techniques. Recent developments in deep learning and artificial neural networks may allow us to address many of these challenges and unlock the information in the EHR. Deep learning emerged as the preferred machine learning approach in machine perception www.nature.com/npjdigitalmed •2018년 1월 구글이 전자의무기록(EMR)을 분석하여, 환자 치료 결과를 예측하는 인공지능 발표 •환자가 입원 중에 사망할 것인지 •장기간 입원할 것인지 •퇴원 후에 30일 내에 재입원할 것인지 •퇴원 시의 진단명
 •이번 연구의 특징: 확장성 •과거 다른 연구와 달리 EMR의 일부 데이터를 pre-processing 하지 않고, •전체 EMR 를 통채로 모두 분석하였음: UCSF, UCM (시카고 대학병원) •특히, 비정형 데이터인 의사의 진료 노트도 분석
  87. 87. • 복잡한 의료 데이터의 분석 및 insight 도출 • 영상 의료/병리 데이터의 분석/판독 • 연속 데이터의 모니터링 및 예방/예측 의료 인공지능의 세 유형
  88. 88. Deep Learning http://theanalyticsstore.ie/deep-learning/
  89. 89. Radiologist
  90. 90. Detection of Diabetic Retinopathy
  91. 91. Skin Cancer
  92. 92. Digital Pathologist
  93. 93. http://www.rolls-royce.com/about/our-technology/enabling-technologies/engine-health-management.aspx#sense 250 sensors to monitor the “health” of the GE turbines
  94. 94. Fig 1. What can consumer wearables do? Heart rate can be measured with an oximeter built into a ring [3], muscle activity with an electromyographi sensor embedded into clothing [4], stress with an electodermal sensor incorporated into a wristband [5], and physical activity or sleep patterns via an accelerometer in a watch [6,7]. In addition, a female’s most fertile period can be identified with detailed body temperature tracking [8], while levels of me attention can be monitored with a small number of non-gelled electroencephalogram (EEG) electrodes [9]. Levels of social interaction (also known to a PLOS Medicine 2016
  95. 95. • 복잡한 의료 데이터의 분석 및 insight 도출 • 영상 의료/병리 데이터의 분석/판독 • 연속 데이터의 모니터링 및 예방/예측 인공지능의 의료 활용
  96. 96. Project Artemis at UIOT
  97. 97. Sugar.IQ 사용자의 음식 섭취와 그에 따른 혈당 변화, 인슐린 주입 등의 과거 기록 기반 식후 사용자의 혈당이 어떻게 변화할지 Watson 이 예측
  98. 98. An Algorithm Based on Deep Learning for Predicting In-Hospital Cardiac Arrest Joon-myoung Kwon, MD;* Youngnam Lee, MS;* Yeha Lee, PhD; Seungwoo Lee, BS; Jinsik Park, MD, PhD Background-—In-hospital cardiac arrest is a major burden to public health, which affects patient safety. Although traditional track- and-trigger systems are used to predict cardiac arrest early, they have limitations, with low sensitivity and high false-alarm rates. We propose a deep learning–based early warning system that shows higher performance than the existing track-and-trigger systems. Methods and Results-—This retrospective cohort study reviewed patients who were admitted to 2 hospitals from June 2010 to July 2017. A total of 52 131 patients were included. Specifically, a recurrent neural network was trained using data from June 2010 to January 2017. The result was tested using the data from February to July 2017. The primary outcome was cardiac arrest, and the secondary outcome was death without attempted resuscitation. As comparative measures, we used the area under the receiver operating characteristic curve (AUROC), the area under the precision–recall curve (AUPRC), and the net reclassification index. Furthermore, we evaluated sensitivity while varying the number of alarms. The deep learning–based early warning system (AUROC: 0.850; AUPRC: 0.044) significantly outperformed a modified early warning score (AUROC: 0.603; AUPRC: 0.003), a random forest algorithm (AUROC: 0.780; AUPRC: 0.014), and logistic regression (AUROC: 0.613; AUPRC: 0.007). Furthermore, the deep learning– based early warning system reduced the number of alarms by 82.2%, 13.5%, and 42.1% compared with the modified early warning system, random forest, and logistic regression, respectively, at the same sensitivity. Conclusions-—An algorithm based on deep learning had high sensitivity and a low false-alarm rate for detection of patients with cardiac arrest in the multicenter study. (J Am Heart Assoc. 2018;7:e008678. DOI: 10.1161/JAHA.118.008678.) Key Words: artificial intelligence • cardiac arrest • deep learning • machine learning • rapid response system • resuscitation In-hospital cardiac arrest is a major burden to public health, which affects patient safety.1–3 More than a half of cardiac arrests result from respiratory failure or hypovolemic shock, and 80% of patients with cardiac arrest show signs of deterioration in the 8 hours before cardiac arrest.4–9 However, 209 000 in-hospital cardiac arrests occur in the United States each year, and the survival discharge rate for patients with cardiac arrest is <20% worldwide.10,11 Rapid response systems (RRSs) have been introduced in many hospitals to detect cardiac arrest using the track-and-trigger system (TTS).12,13 Two types of TTS are used in RRSs. For the single-parameter TTS (SPTTS), cardiac arrest is predicted if any single vital sign (eg, heart rate [HR], blood pressure) is out of the normal range.14 The aggregated weighted TTS calculates a weighted score for each vital sign and then finds patients with cardiac arrest based on the sum of these scores.15 The modified early warning score (MEWS) is one of the most widely used approaches among all aggregated weighted TTSs (Table 1)16 ; however, traditional TTSs including MEWS have limitations, with low sensitivity or high false-alarm rates.14,15,17 Sensitivity and false-alarm rate interact: Increased sensitivity creates higher false-alarm rates and vice versa. Current RRSs suffer from low sensitivity or a high false- alarm rate. An RRS was used for only 30% of patients before unplanned intensive care unit admission and was not used for 22.8% of patients, even if they met the criteria.18,19 From the Departments of Emergency Medicine (J.-m.K.) and Cardiology (J.P.), Mediplex Sejong Hospital, Incheon, Korea; VUNO, Seoul, Korea (Youngnam L., Yeha L., S.L.). *Dr Kwon and Mr Youngnam Lee contributed equally to this study. Correspondence to: Joon-myoung Kwon, MD, Department of Emergency medicine, Mediplex Sejong Hospital, 20, Gyeyangmunhwa-ro, Gyeyang-gu, Incheon 21080, Korea. E-mail: kwonjm@sejongh.co.kr Received January 18, 2018; accepted May 31, 2018. ª 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. DOI: 10.1161/JAHA.118.008678 Journal of the American Heart Association 1 ORIGINAL RESEARCH byguestonJune28,2018http://jaha.ahajournals.org/Downloadedfrom
  99. 99. •환자 수: 86,290 •cardiac arrest: 633 •Input: Heart rate, Respiratory rate, Body temperature, Systolic Blood Pressure (source: VUNO) Cardiac Arrest Prediction Accuracy
  100. 100. •대학병원 신속 대응팀에서 처리 가능한 알림 수 (A, B 지점) 에서 더 큰 정확도 차이를 보임 •A: DEWS 33.0%, MEWS 0.3% •B: DEWS 42.7%, MEWS 4.0% (source: VUNO) APPH(Alarms Per Patients Per Hour) (source: VUNO) Less False Alarm
  101. 101. (source: VUNO) 시간에 따른 DEWS 예측 변화
  102. 102. Cardiogram •실리콘밸리의 Cardiogram 은 애플워치로 측정한 심박수 데이터를 바탕으로 서비스 •2016년 10월 Andressen Horowitz 에서 $2m의 투자 유치
  103. 103. Passive Detection of Atrial Fibrillation Using a Commercially Available Smartwatch Geoffrey H. Tison, MD, MPH; José M. Sanchez, MD; Brandon Ballinger, BS; Avesh Singh, MS; Jeffrey E. Olgin, MD; Mark J. Pletcher, MD, MPH; Eric Vittinghoff, PhD; Emily S. Lee, BA; Shannon M. Fan, BA; Rachel A. Gladstone, BA; Carlos Mikell, BS; Nimit Sohoni, BS; Johnson Hsieh, MS; Gregory M. Marcus, MD, MAS IMPORTANCE Atrial fibrillation (AF) affects 34 million people worldwide and is a leading cause of stroke. A readily accessible means to continuously monitor for AF could prevent large numbers of strokes and death. OBJECTIVE To develop and validate a deep neural network to detect AF using smartwatch data. DESIGN, SETTING, AND PARTICIPANTS In this multinational cardiovascular remote cohort study coordinated at the University of California, San Francisco, smartwatches were used to obtain heart rate and step count data for algorithm development. A total of 9750 participants enrolled in the Health eHeart Study and 51 patients undergoing cardioversion at the University of California, San Francisco, were enrolled between February 2016 and March 2017. A deep neural network was trained using a method called heuristic pretraining in which the network approximated representations of the R-R interval (ie, time between heartbeats) without manual labeling of training data. Validation was performed against the reference standard 12-lead electrocardiography (ECG) in a separate cohort of patients undergoing cardioversion. A second exploratory validation was performed using smartwatch data from ambulatory individuals against the reference standard of self-reported history of persistent AF. Data were analyzed from March 2017 to September 2017. MAIN OUTCOMES AND MEASURES The sensitivity, specificity, and receiver operating characteristic C statistic for the algorithm to detect AF were generated based on the reference standard of 12-lead ECG–diagnosed AF. RESULTS Of the 9750 participants enrolled in the remote cohort, including 347 participants with AF, 6143 (63.0%) were male, and the mean (SD) age was 42 (12) years. There were more than 139 million heart rate measurements on which the deep neural network was trained. The deep neural network exhibited a C statistic of 0.97 (95% CI, 0.94-1.00; P < .001) to detect AF against the reference standard 12-lead ECG–diagnosed AF in the external validation cohort of 51 patients undergoing cardioversion; sensitivity was 98.0% and specificity was 90.2%. In an exploratory analysis relying on self-report of persistent AF in ambulatory participants, the C statistic was 0.72 (95% CI, 0.64-0.78); sensitivity was 67.7% and specificity was 67.6%. CONCLUSIONS AND RELEVANCE This proof-of-concept study found that smartwatch photoplethysmography coupled with a deep neural network can passively detect AF but with some loss of sensitivity and specificity against a criterion-standard ECG. Further studies will help identify the optimal role for smartwatch-guided rhythm assessment. JAMA Cardiol. doi:10.1001/jamacardio.2018.0136 Published online March 21, 2018. Editorial Supplemental content and Audio Author Affiliations: Division of Cardiology, Department of Medicine, University of California, San Francisco (Tison, Sanchez, Olgin, Lee, Fan, Gladstone, Mikell, Marcus); Cardiogram Incorporated, San Francisco, California (Ballinger, Singh, Sohoni, Hsieh); Department of Epidemiology and Biostatistics, University of California, San Francisco (Pletcher, Vittinghoff). Corresponding Author: Gregory M. Marcus, MD, MAS, Division of Cardiology, Department of Medicine, University of California, San Francisco, 505 Parnassus Ave, M1180B, San Francisco, CA 94143- 0124 (marcusg@medicine.ucsf.edu). Research JAMA Cardiology | Original Investigation (Reprinted) E1 © 2018 American Medical Association. All rights reserved.
  104. 104. • ZIO Patch • 2009년에 FDA에서 인허가 받은 의료기기 • 최대 2주까지 붙이고 다니면서 지속적으로 심전도를 측정

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