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“Leveraging Biomedical Big Data:
       Quantified Self & Beyond”

                          Invited Talk
                          FutureMed
                      Singularity University
                      NASA Ames Campus
                        February 5, 2013

                             Dr. Larry Smarr
Director, California Institute for Telecommunications and Information
                                Technology
                       Harry E. Gruber Professor,
             Dept. of Computer Science and Engineering
                                                                        1
                 Jacobs School of Engineering, UCSD
Where I Believe We are Headed: Predictive,
Personalized, Preventive, & Participatory Medicine

                                    I am Leroy Hood’s Lab Rat!




     www.newsweek.com/2009/06/26/a-doctor-s-vision-of-the-future-of-medicine.html
I Arrived in La Jolla in 2000of My Body andin the Midwest
   By Measuring the State After 20 Years “Tuning” It
     Using Nutrition and Exercise, Ithe Obesity Trend
     and Decided to Move Against Became Healthier
       Age                                   Age                                  Age
        41                                    51                                   61

                                  1999                                                  2010
                                   2000
                               1999




                1989



        I Reversed My Body’s Decline By
        Quantifying and Altering Nutrition and Exercise

        http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf
From Measuring Macro-Variables
to Measuring Your Internal Variables




  www.technologyreview.com/biomedicine/39636
From One to a Billion Data Points Defining Me:
The Exponential Rise in Body Data in Just One Decade!

                                                   Billion:Microbial Genome
                                                           My Full DNA,
                                                      MRI/CT Images




              Improving Body
                                              SNPs
                          Million: My DNA SNPs,
                                 Zeo, FitBit
                                               Discovering Disease
                        Blood
                       Variables

             One:                  Hundred: My Blood Variables
       Weight Weight
          My
Visualizing Time Series of
150 LS Blood and Stool Variables, Each Over 5 Years
                                 Calit2 64 megapixel VROOM
Only One of My Blood Measurements
Was Far Out of Range--Indicating Chronic Inflammation

           Episodic Peaks in Inflammation                      27x
           Followed by Spontaneous Drop




                               15x



                                      Antibiotics

    5x

                                                     Antibiotics
                        Normal Range CRP < 1




         Complex Reactive Protein (CRP) is a Blood Biomarker
               for Detecting Presence of Inflammation
By Quantifying Stool Measurements Over Time
I Discovered Source of Inflammation Was Likely in Colon
                                          124x Upper Limit     Typical
                                                             Lactoferrin
                                                              Value for
           Stool Samples Analyzed                              Active
        by www.yourfuturehealth.com                              IBD




                  Normal Range
                   <7.3 µg/mL




          Lactoferrin is a Sensitive and Specific Biomarker for
        Detecting Presence of Inflammatory Bowel Disease (IBD)
Startup WellnessFX Enables You to
  Track Your Own Blood Variables




      LS Values from WellnessFX.com
From Vials of Blood for a Few Variables
to Thousands of Proteins from a Single Drop




              www.somalogic.com/
Integrative Personal Omics Profiling
Reveals Details of Clinical Onset of Viruses and Diabetes
                                    Cell 148, 1293–1307, March 16, 2012

                                          •   Michael Snyder,
                                              Chair of Genomics
                                              Stanford Univ.
                                          •   Genome 140x
                                              Coverage
                                          •   Blood Tests 20
                                              Times in 14 Months
                                               – tracked nearly
                                                 20,000 distinct
                                                 transcripts coding
                                                 for 12,000 genes
                                               – measured the
                                                 relative levels of
                                                 more than 6,000
                                                 proteins and 1,000
                                                 metabolites in
                                                 Snyder's blood
Confirming the IBD (Crohn’s) Hypothesis:
         Finding the “Smoking Gun” with MRI Imaging
      Liver                              I Obtained the MRI Slices
                  Transverse Colon
                                       From UCSD Medical Services
                                      and Converted to Interactive 3D
                                                Working With
         Small Intestine              Calit2 Staff & DeskVOX Software
                                                                  Descending Colon




 MRI Jan 2012
Cross Section
                  Diseased Sigmoid Colon




                                                                       Major Kink
                                               Sigmoid Colon
                                           Threading Iliac Arteries
Interactive Visualization and 3D Printed Hard Copy
                 from LS MRI Data




             Research: Calit2 FutureHealth Team
Why Did I Have an Autoimmune Disease like IBD?


      Despite decades of research,
     the etiology of Crohn's disease
            remains unknown.
      Its pathogenesis may involve
      a complex interplay between
              host genetics,
           immune dysfunction,
  and microbial or environmental factors.
      --The Role of Microbes in Crohn's Disease

     So I Set Out to Quantify All Three!
             Paul B. Eckburg & David A. Relman
              Clin Infect Dis. 44:256-262 (2007) 
Single Nucleotide Polymorphisms (SNPs) Make Up
    About 90% of All Human Genetic Variation




Person A

                                     SNPs Occur Every
                                      100 to 300 Bases
                                     Along Human DNA

Person B




     www.23andme.com Tracks One Million SNPs
Soon a Trillion SNPs in a Startup!
       Incredible Opportunities for Crowdsourcing




23andMe looks at 1,000,000 SNPs scattered across the 23 pairs of chromosomes
I Wondered if Crohn’s is an Autoimmune Disease,
  Did I Have a Personal Genomic Polymorphism?
            From www.23andme.com            Polymorphism in
                                     Interleukin-23 Receptor Gene
                                          — 80% Higher Risk
             ATG16L1
                                          of Pro-inflammatory
                                           Immune Response
                   IRGM




     NOD2        SNPs Associated with CD
Crohn’s May be a Related Set of Diseases
        Driven by Different SNPs

    NOD2 (1)
   rs2066844
                                        Female
                                       CD Onset
                                    At 20-Years Old




                                    Il-23R
                                  rs1004819



                                        Me-Male
                                       CD Onset
                                    At 60-Years Old
Imagine Crowdsourcing 23andme SNPs
For Even a Small Portion of Crohnology!




Hear Crohnology Founder Sean Ahrens Friday
           www.crohnology.com
Putting Multiple Immunological Biomarker Time Series
     Together, Reveals Major Immune Dysfunction




     Green : Inside Range
     Orange: 1-10x Over
     Red: 10-100x Over
     Purple: >100x Over




               Source: Calit2 Future Health Expedition Team
Four Immune Biomarkers Over Time
 Compared with Four Signs/Symptoms




Here Immune biomarkers are normalized 0 to 1,
  with 1 being the highest value in five years



      Source: Photo of Calit2 64-megapixel VROOM
Intense Scientific Research is Underway
on Understanding the Human Microbiome




   June 8, 2012             June 14, 2012
Microbes are 90% of Your Cells-So I Set Out
to Determine My Gut Microbes & Their Time Variation
                              Shipped Stool Sample
                               December 28, 2011

                                    I Received
                             a Disk Drive April 3, 2012
                             With 35 GB FASTQ Files

                               Weizhong Li, UCSD
                                 NGS Pipeline:
                                  230M Reads
                               Only 0.2% Human

                           Required 1/2 cpu-yr at SDSC
                              Per Person Analyzed!
Phyla Gut Microbial Abundance:
         LS, Crohn’s, UC, and Healthy Subjects
         Source: Weizhong Li, UCSD; Calit2 FuturePatient Expedition




LS   Crohn’s       Ulcerative            Healthy
                    Colitis

                      Toward Noninvasive
                  Microbial Ecology Diagnostics
LS Gut Microbe Species 12/28/11 (red)
 compared to Average of Healthy Subjects (blue)




Derived from metagenomic sequencing of LS stool sample.
                  Each species is a bar,
             height is logarithmic abundance,
          species are divided into microbial phyla
           Source: Photo of Calit2 64-megapixel VROOM
Top 20 Most Abundant Microbial Species
       In LS vs. Healthy Subject
152x                                            Number Above
                                             LS Blue Bar is Multiple
                                               of LS Abundance
   765x
                                             Compared to Average
       148x                                   Healthy Abundance
                                                  Per Species
          849x
             483x
                220x
                  201x169x
                         522x




  Source: Sequencing JCVI; Analysis Weizhong Li, UCSD
           LS December 28, 2012 Stool Sample
200 LS Gut Microbe Species at 3 Times
              12/28/11, 4/3/12, 8/7/12




              Red is at Highest Value of CRP
Blue is the Day After End of Antibiotic/Prednisone Therapy
                Green is Four Months Later

            Source: Photo of Calit2 64-megapixel VROOM
Closeup of Uncommon LS Microbes
                12/28/11 Stool Sample
                                              Two separate
  45x                                        research teams
Reduced                                         have found
                                               strikingly high
  By              8%              90x         concentrations
Therapy        Increased        Reduced     of Fusobacterium
                                            in tumor samples
                  By              By          collected from
                Therapy         Therapy     colorectal cancer
                                                  patients.
                                            October 18, 2011
From Current IBD Therapies
               to Novel Systems Approaches
• Current Therapies
  –   Diet
  –   Probiotics
  –   Drugs
  –   Surgery
• Emerging Directions
  –   Microbiome Transfer
  –   Synthetic Microbiomes
  –   Ecological Gardening
  –   Targeted Bacteriophage
From War
      to Gardening




  “I would like to lose the language of warfare,”
     said Julie Segre, a senior investigator at
the National Human Genome Research Institute.
      ”It does a disservice to all the bacteria
            that have co-evolved with us
  and are maintaining the health of our bodies.”
From the Single “Bad” Microbe Medical Target
    to the Microbiome Ecology Paradigm
           Sci Transl Med 4, 137rv5 (2012);




            Science 336, 1255 (2012)


   Problem of Alternative Stable States
     In Ecological System Dynamics
Next Decade Will See New Microbiome
         “Gardening Tools”



                                             August 7, 2012




          Journal of Nanotechnology (2012)
Startups Are Enabling Genomic Sequencing
            of Your Microbiome



                         http://ubiome.com/
DIY Systems Biology -
                                    Toward P4 Healthcare

                                                                 Over 1000 Downloads So Far




         Download pdfs from Journal:
http://onlinelibrary.wiley.com/doi/10.1002/biot.201100495/full

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Frank Würthwein - NRP and the Path forward
 

Leveraging Biomedical Big Data: Quantified Self & Beyond

  • 1. “Leveraging Biomedical Big Data: Quantified Self & Beyond” Invited Talk FutureMed Singularity University NASA Ames Campus February 5, 2013 Dr. Larry Smarr Director, California Institute for Telecommunications and Information Technology Harry E. Gruber Professor, Dept. of Computer Science and Engineering 1 Jacobs School of Engineering, UCSD
  • 2. Where I Believe We are Headed: Predictive, Personalized, Preventive, & Participatory Medicine I am Leroy Hood’s Lab Rat! www.newsweek.com/2009/06/26/a-doctor-s-vision-of-the-future-of-medicine.html
  • 3. I Arrived in La Jolla in 2000of My Body andin the Midwest By Measuring the State After 20 Years “Tuning” It Using Nutrition and Exercise, Ithe Obesity Trend and Decided to Move Against Became Healthier Age Age Age 41 51 61 1999 2010 2000 1999 1989 I Reversed My Body’s Decline By Quantifying and Altering Nutrition and Exercise http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf
  • 4. From Measuring Macro-Variables to Measuring Your Internal Variables www.technologyreview.com/biomedicine/39636
  • 5. From One to a Billion Data Points Defining Me: The Exponential Rise in Body Data in Just One Decade! Billion:Microbial Genome My Full DNA, MRI/CT Images Improving Body SNPs Million: My DNA SNPs, Zeo, FitBit Discovering Disease Blood Variables One: Hundred: My Blood Variables Weight Weight My
  • 6. Visualizing Time Series of 150 LS Blood and Stool Variables, Each Over 5 Years Calit2 64 megapixel VROOM
  • 7. Only One of My Blood Measurements Was Far Out of Range--Indicating Chronic Inflammation Episodic Peaks in Inflammation 27x Followed by Spontaneous Drop 15x Antibiotics 5x Antibiotics Normal Range CRP < 1 Complex Reactive Protein (CRP) is a Blood Biomarker for Detecting Presence of Inflammation
  • 8. By Quantifying Stool Measurements Over Time I Discovered Source of Inflammation Was Likely in Colon 124x Upper Limit Typical Lactoferrin Value for Stool Samples Analyzed Active by www.yourfuturehealth.com IBD Normal Range <7.3 µg/mL Lactoferrin is a Sensitive and Specific Biomarker for Detecting Presence of Inflammatory Bowel Disease (IBD)
  • 9. Startup WellnessFX Enables You to Track Your Own Blood Variables LS Values from WellnessFX.com
  • 10. From Vials of Blood for a Few Variables to Thousands of Proteins from a Single Drop www.somalogic.com/
  • 11. Integrative Personal Omics Profiling Reveals Details of Clinical Onset of Viruses and Diabetes Cell 148, 1293–1307, March 16, 2012 • Michael Snyder, Chair of Genomics Stanford Univ. • Genome 140x Coverage • Blood Tests 20 Times in 14 Months – tracked nearly 20,000 distinct transcripts coding for 12,000 genes – measured the relative levels of more than 6,000 proteins and 1,000 metabolites in Snyder's blood
  • 12. Confirming the IBD (Crohn’s) Hypothesis: Finding the “Smoking Gun” with MRI Imaging Liver I Obtained the MRI Slices Transverse Colon From UCSD Medical Services and Converted to Interactive 3D Working With Small Intestine Calit2 Staff & DeskVOX Software Descending Colon MRI Jan 2012 Cross Section Diseased Sigmoid Colon Major Kink Sigmoid Colon Threading Iliac Arteries
  • 13. Interactive Visualization and 3D Printed Hard Copy from LS MRI Data Research: Calit2 FutureHealth Team
  • 14. Why Did I Have an Autoimmune Disease like IBD? Despite decades of research, the etiology of Crohn's disease remains unknown. Its pathogenesis may involve a complex interplay between host genetics, immune dysfunction, and microbial or environmental factors. --The Role of Microbes in Crohn's Disease So I Set Out to Quantify All Three! Paul B. Eckburg & David A. Relman Clin Infect Dis. 44:256-262 (2007) 
  • 15. Single Nucleotide Polymorphisms (SNPs) Make Up About 90% of All Human Genetic Variation Person A SNPs Occur Every 100 to 300 Bases Along Human DNA Person B www.23andme.com Tracks One Million SNPs
  • 16. Soon a Trillion SNPs in a Startup! Incredible Opportunities for Crowdsourcing 23andMe looks at 1,000,000 SNPs scattered across the 23 pairs of chromosomes
  • 17. I Wondered if Crohn’s is an Autoimmune Disease, Did I Have a Personal Genomic Polymorphism? From www.23andme.com Polymorphism in Interleukin-23 Receptor Gene — 80% Higher Risk ATG16L1 of Pro-inflammatory Immune Response IRGM NOD2 SNPs Associated with CD
  • 18. Crohn’s May be a Related Set of Diseases Driven by Different SNPs NOD2 (1) rs2066844 Female CD Onset At 20-Years Old Il-23R rs1004819 Me-Male CD Onset At 60-Years Old
  • 19. Imagine Crowdsourcing 23andme SNPs For Even a Small Portion of Crohnology! Hear Crohnology Founder Sean Ahrens Friday www.crohnology.com
  • 20. Putting Multiple Immunological Biomarker Time Series Together, Reveals Major Immune Dysfunction Green : Inside Range Orange: 1-10x Over Red: 10-100x Over Purple: >100x Over Source: Calit2 Future Health Expedition Team
  • 21. Four Immune Biomarkers Over Time Compared with Four Signs/Symptoms Here Immune biomarkers are normalized 0 to 1, with 1 being the highest value in five years Source: Photo of Calit2 64-megapixel VROOM
  • 22. Intense Scientific Research is Underway on Understanding the Human Microbiome June 8, 2012 June 14, 2012
  • 23. Microbes are 90% of Your Cells-So I Set Out to Determine My Gut Microbes & Their Time Variation Shipped Stool Sample December 28, 2011 I Received a Disk Drive April 3, 2012 With 35 GB FASTQ Files Weizhong Li, UCSD NGS Pipeline: 230M Reads Only 0.2% Human Required 1/2 cpu-yr at SDSC Per Person Analyzed!
  • 24. Phyla Gut Microbial Abundance: LS, Crohn’s, UC, and Healthy Subjects Source: Weizhong Li, UCSD; Calit2 FuturePatient Expedition LS Crohn’s Ulcerative Healthy Colitis Toward Noninvasive Microbial Ecology Diagnostics
  • 25. LS Gut Microbe Species 12/28/11 (red) compared to Average of Healthy Subjects (blue) Derived from metagenomic sequencing of LS stool sample. Each species is a bar, height is logarithmic abundance, species are divided into microbial phyla Source: Photo of Calit2 64-megapixel VROOM
  • 26. Top 20 Most Abundant Microbial Species In LS vs. Healthy Subject 152x Number Above LS Blue Bar is Multiple of LS Abundance 765x Compared to Average 148x Healthy Abundance Per Species 849x 483x 220x 201x169x 522x Source: Sequencing JCVI; Analysis Weizhong Li, UCSD LS December 28, 2012 Stool Sample
  • 27. 200 LS Gut Microbe Species at 3 Times 12/28/11, 4/3/12, 8/7/12 Red is at Highest Value of CRP Blue is the Day After End of Antibiotic/Prednisone Therapy Green is Four Months Later Source: Photo of Calit2 64-megapixel VROOM
  • 28. Closeup of Uncommon LS Microbes 12/28/11 Stool Sample Two separate 45x research teams Reduced have found strikingly high By 8% 90x concentrations Therapy Increased Reduced of Fusobacterium in tumor samples By By collected from Therapy Therapy colorectal cancer patients. October 18, 2011
  • 29. From Current IBD Therapies to Novel Systems Approaches • Current Therapies – Diet – Probiotics – Drugs – Surgery • Emerging Directions – Microbiome Transfer – Synthetic Microbiomes – Ecological Gardening – Targeted Bacteriophage
  • 30. From War to Gardening “I would like to lose the language of warfare,” said Julie Segre, a senior investigator at the National Human Genome Research Institute. ”It does a disservice to all the bacteria that have co-evolved with us and are maintaining the health of our bodies.”
  • 31. From the Single “Bad” Microbe Medical Target to the Microbiome Ecology Paradigm Sci Transl Med 4, 137rv5 (2012); Science 336, 1255 (2012) Problem of Alternative Stable States In Ecological System Dynamics
  • 32. Next Decade Will See New Microbiome “Gardening Tools” August 7, 2012 Journal of Nanotechnology (2012)
  • 33. Startups Are Enabling Genomic Sequencing of Your Microbiome http://ubiome.com/
  • 34. DIY Systems Biology - Toward P4 Healthcare Over 1000 Downloads So Far Download pdfs from Journal: http://onlinelibrary.wiley.com/doi/10.1002/biot.201100495/full