Virtual Health Nucleus A scalable, multimodal, …...David S. Karow, MD, PhD Chief of Radiogenomics and Interim CEO, Human Longevity, Inc. Associate Professor of Radiology, UC San

David S. Karow, MD, PhD

Chief of Radiogenomics and Interim CEO, Human Longevity, Inc.

Associate Professor of Radiology, UC San Diego

Virtual Health NucleusTM

A scalable, multimodal, predictive analytics

platform that enables partners to provide pre-

symptomatic diagnosis

CONFIDENTIAL - NOT FOR DISTRIBUTION 2

Our Mission:

To use precision health analytics to extend the high quality human lifespan.


The “Genomic Era”, June 26, 2000: Bill Clinton on the sequencing of the human genome: It will “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases.”

Our Purpose: Extend the Healthy Human Lifespan


Sequencers

– Illumina

• 8 NovaSeq 6000 (64,000 Genomes/Yr)

• 6 HiSeq X (8,000 Genomes/Yr)

• 4 HiSeq 4000 (55,000 Exomes/Yr)

– ThermoFisher

• Ion S5 System

40,000 Whole genomes sequenced

CAP and CLIA accredited

WGS and tumor exome

Human Longevity Sequencing Laboratories


Software to provide HLA typing from Illumina

sequence data

(Xie et al, PNAS 2017)

Patent: Methods of human leukocyte antigen

typing

Protocols and technologies for microbiome analysis

(Jones et al, PNAS 2015;

Anderson et al, Sci Rep 2016)

Patent: Use of a microbiome profile to detect

liver disease

Deep sequencing of 10,000 human genomes

(Telenti et al, PNAS 2016)

The human non-coding genome defined by genetic

diversity

(di Iulio et al. Nature Genetics)

Patent: Methods of determining genomic health

risk

Identification of functional domains in proteins

(Hicks et al, BioRxiv 2017)

Patent: Structural Predictions of Proteins

Software to provide Short Tandem Repeat calls from

sequence data

(Tang et al, AJHG 2017)

Patent: Determination of STR length by short

read sequencing

Machine learning tools to predict physical traits

(Lippert et al, PNAS 2017)

Patent: Identification of individuals by trait

prediction from the genome

https://search.hli.io/

Patent: Genomic, metabolomic, and

microbiomic search engine

Select Genomic IP and Publications


Science April 2018 PNAS April 2018

Recent Publications

HLI has deep roots in research and we continue to translate our findings to clinically relevant analytical tools


Whole-genome (30x)

Microbiome

Family and Med Hx

Metabolomics

Serum Labs

Gait & Balance

Neuropsychiatric

Advanced Imaging (full

body MRI, Coronary CT,

cardiac MRI)

4D ECHO, EKG

Cardiac Rhythm Monitor

Multi-Modality Phenotype Data Gathering

Gathering Deep Phenotype to understand our genome


2% with a new brain or aortic aneurysm

2% with a new tumor suspected or confirmed, many high grade cancers and early stage.

19% with moderate atherosclerotic coronary calcifications (Agatston

score>100). 3.1% with score of 400-1000; 1.9% with score >1000. Based on 384 clients.

43% with elevated liver fat, mostly non-alcoholic fatty liver disease and associated with

increased visceral abdominal fat.

84% are genetic carriers for recessive diseases. 17% have a rare genetic

mutation that affects their health. (Autosomal dominant rare genetic mutations)

3.4% with newly found Atrial fibrillation, BBB, or high grade AV block from

iRhythm cardiac monitoring.

14.8% with aberrant cardiac structure/function findings

Health Nucleus Actionable Results from 1253 “healthy” Clients


Client: 79 year old

healthy male

Finding: Diffuse

lymphadenopathy

with biopsy showing

follicular lymphoma

Case Study: Lymphoma


Client: 34 year old

healthy female

Finding: 1.3 cm left

thyroid nodule on

MRI. Biopsy

showed papillary

thyroid cancer

Case Study: Thyroid Cancer

Trachea

Cervical spinal cord

Normal right

thyroid lobe


Client: 54 year old

healthy non-

smoking female

client

Finding: 2 cm right

lung mass on MRI.

Biopsy confirmed

adenocarcinoma

Case Study: Lung Adenocarcinoma


Overall Health Nucleus detection rate for prostate cancer = 2.5%

T2 DWI

Male Clients 59 and older: 353

9 diagnosed with cancer = 2.5%

PPV: 90%

Specificity: 99.7%

1 false positive, 1 false negative

Case Study: Prostate Cancer


9

diagnosed

in HN

30 with pre-

HN history

of PCa

Total of 39 Health nucleus clients with PCa. 23% has reportable variants (P=2, VUS-N=5, risk=5)

Age Gene c.HGVS AR repeat # FH Damaging Clinical Signiciance

68 XRCC2 c.667T>C 21 Y Y VUS-N

70 RAD51C c.485G>A 7 . Y VUS-N

66 BRCA2 c.81-3351A>G 21 N Y VUS

64 HOXB13 c.-4696G>A 19 Y Y VUS

59 AR 13 N . risk

74 TP53 c.844C>T 23 Y Y P

74 ATM c.3078-1G>A 21 Y Y P

69 ATM c.2720G>T 22 Y Y VUS-N

81 RNASEL c.1199G>C 21 Y Y VUS-N

67 NBN c.1262T>C 23 Y N VUS-N

71 PALB2 c.3538A>G 17 N Y VUS

62 MLH1 c.1558+4286_1558+4289delCTGA 21 Y Y VUS

87 BRCA1 c.5341-2419G>A 16 N Y VUS

77 ATM c.8672-2924G>C 20 N Y VUS

67 AR 17 Y . risk

1. VUS-N are at the borderline of ACMG guidelines of likely pathogenic classification (i.e. 1-2 minor evidence level are needed).

2. Clients' family history fits NCCN guideline on familial prostate cancer and variants have sufficient evidence to suspect disease.

Rare Variants identified in Prostate cancer clients from WGS


Client: 45 year old

healthy female

Finding: Fatty liver

(30%) and

increased Visceral

Adipose tissue

(VAT); at risk for

cirrhosis

Case Study: Fatty Liver and Increased Visceral Adipose Tissue

NAFLD = Non alcoholic fatty liver disease. Left untreated, can progress to cirrhosis


Client: 49 yo female

Finding: Newly

found 8 mm left

cavernous ICA

aneurysm

Case Study: Brain Aneurysm


Client: 45 year old

‘healthy’ female

• Finding: Calcium score

of 131, at the 99% for

age/gender

• Majority of disease is in

the LAD

• The 10-year CAD event

risk is 5.9 % for this patient

as opposed to 1.9% if we

did not factor in calcium

score.

Case Study: Advanced coronary artery disease


Variant type Individuals

Medically Significant Variant (MSV) 17.3%

MSV + F2, F5 and ALDH2 24.3% ~ 50% of

variants confirmed

by phenotype

(PMH, FH, MRI, Dx tests)

Rare Genetic Findings from WGS in 24.3% of Clients

Conditions Genes

Cancer

ATM, BRCA1, BRCA2, BRIP1,

BARD1, CHEK2, EPCAM, FH,

GLMN, HOXB13, LZTR1,

MSH6, NBN, NF1, PMS2,

RAD50 RAD51C, RB1,

RECQL, TP53

Cardiovascular

APOB, APOC3, DSC2, ENG,

GPD1L, KCNE2, KCNQ1,

LDLR, LMNA, LPL, MYBPC3,

MYH7, MYL2, NPC1L1,

PCSK9, PKP2, RBM20,

SCN1B, TNNT2, TTN, TTR

Endocrine

ABCC8, GLMN, HNF1A,

HNF1B, INSR, MC4R,

NEUROD1, NOBOX, NR3C1,

PCSK1, PPP1R3A, PROK2


Client: 60-year-old male with digestive

issues/ bloating, and chronic sinus

infections

• Findings:

• MRI: Tree in bud nodularity at the right

mid and upper lung zone. Mild

bronchial wall thickening

• WGS: Compound heterozygous mutations in the CFTR gene

• c.3846G>A (p.Trp1282*) - well known

mutation causative for classic CF

• c.3454G>C (p.Asp1152His) – variable,

can cause congenital bilateral

absence of the vas deferens or

atypical CF

Case Study: Atypical Cystic Fibrosis (CF)


Client: 54-year-old male, Asian

ancestry; personal history of premature

atrial contractions; family history: father

with CAD, coronary bypass; maternal

grandfather and maternal uncle with stroke

• Findings:

• High calcium score of 111 (85 to 93 percentile)

• Elevated Total (254mg/dL) and LDL

Cholesterol (167mg/dL)

• WGS: autosomal dominant variant in the PCSK9 gene

• c.10G>A (p.Val4Ile) – found in

Japanese FH individuals

Case Study: Familial Hypercholesterolemia (FH)


Client: ‘Healthy’ 49-year-old male;

History of hyperlipidemia, eosinophilic

esophagitis, and no other major

medical concern; Fainting during

swimming and multiple events of syncope (first event happened at 18).

• Findings:

• WGS: Likely pathogenic KCNQ1 (c.926C>T) for LQT1 (Long QT syndrome

1)

• Electrocardiography (ECG): QT/QTc -

490/464, prolonged QTc Interval.

Case Study: Long QT Syndrome

Nat Med. 2004, 10:463-4


Notes: 1Significant findings that are actionable include findings requiring immediate or near-term follow-up and intervention; 2Long-term clinical findings include discoveries requiring medical attention or monitoring but not immediately

life threatening; 3Clients screened for the first time;

Significant

findings that

are

actionable1 in

14.4% of

the clients we

screen3

Long-term

value

findings2 in

40%

of the

clients we

screen3

Health Nucleus identified clinical findings in 40% of clients


0

20

40

60

80

100

Without Screening With HN

Ave

rage

Pro

ject

ed

fiv

e y

ear

su

rviv

al (

%)

0 20 40 60 80 100

Subdural hematoma

High grade prostate…

Lymphoma

Thyroid cancer

Transitional cell…

Lung cancer

Artial fib

Renal cell carcinoma

14.4% of HN clients with Immediate Value Findings

Total Years Projected Gained for 14.4% = 129.41– 285.7

Projected years gained per individual with Immediate Value Findings = 0.72 – 8.51 years

* For individuals with significant findings only. Assumes that no screening would

result in a late stage diagnosis.

Without screening

With HN

Five Year Survival (%)

Projected five year survival after diagnosis (%)

Meaningful Extension of Life Through Using the Health

Nucleus Platform: 1-9 years of life added


Health Nucleus Overview


Catch and prevent

disease early and

avoid premature death

Reduce the risk of

catastrophic costs

associated with disease

and treatment

Extend healthy life span

The impact…

Health Nucleus is a first-of- its-kind discovery

center that combines whole genome

sequencing with whole body MRI for early

detection and risk assessment

Machine learning-based integrated diagnostics

predict lifetime and short term risk of chronic age

related disease

Case review done by expert team of geneticists,

bioinformaticians, radiologists & primary care

physicians

Establishes unprecedented health baseline

Health Nucleus: A Prototype for Precision Wellness


The Health Nucleus establishes a health baseline, identifies health risk, and directs lifestyle and care treatments in order to prevent and/or mitigate life and financial risks

BASELINE HEALTH ASSESSMENT

Whole genome

sequencing

Full body and

brain MRI

Core laboratory

analysis Microbiome

Analysis

Colorectal Cancer

Screen

Coronary calcium

scoring (CT scan)

Cardiac

rhythm monitor

Medical History

ANNUAL FOLLOW-UP

Updated

genomics report

Full body and

brain MRI

Core laboratory

analysis

Microbiome

Analysis

(Optional)

Health Nucleus Core

Optional


* Ages 50 – 74, 2015 in USA; Adapted from Institute of Health Metrics and Evaluation, University of Washington.

http://www.healthdata.org/results/data-visualizations

MALE

39% RISK OF DEATH*

CARDIOVASCULAR 30%

CANCER 33%

FEMALE

24% RISK OF DEATH*

CANCER 40%

CARDIOVASCULAR 23%

NEUROLOGIC 3%

CIRRHOSIS 5%

DIABETES 7%

RESPIRATORY 6%

OTHER 16%

RESPIRATORY 8%

DIABETES 8%

CIRRHOSIS 4%

NEUROLOGIC 4%

OTHER 13%

Problem: 1/3 of people who live to age 50 do not live to 75

Preventable premature mortality from chronic age related disease


Solution: Data-driven precision health platform

Code: Family History

Integration:

Physician

Core: Physical

exam

Last 30+ years

Code: Whole genome sequencing

Integration: AI &

Machine Learning

Core: Whole Body

quantitative MRI

biomarkers

Next generation

Understanding your code and your core through whole genome sequencing and whole body MRI become the

chief components driving downstream preventative, personalized decision support


Whole Body MRI

Derivation of Quantitative Biomarkers & Screening


Precision Medicine Screening:

WGS + Imaging (Perkins et al. PNAS)

Provisional patent: Visualization tool for

cancer screening based using DWI-MRI signal

normalization

Provisional patent: Integrated Risk Model for Dementia using imaging and genetic biomarkers

Provisional patent: Fully Automated Body Composition from MRI-derived Dixon Imaging

Provisional patent: Systems and methods for

measuring obesity using metabolome analysis

Profound perturbation of the human metabolome by obesity (Cirulli et al. under review)

Provisional patent: Neural Networks for 3D

brain MRI Volumetric Segmentation and

Parcellated Surface representations

Provisional patent: Multimodal Personalized Recommenders for Disease Risk

Select IP and publications, beyond genomics

CONFIDENTIAL - NOT FOR DISTRIBUTION 30 *Provisional Patent

Fully Automated Body

Composition from MRI-derived Dixon Imaging

Fat and muscle biomarkers for Diabetes


Quantitative volume assessment: Biomarkers for Dementia

Provisional Patent

HLI’s Approach < 10 mins Atlas-based approaches 3-12 hours

HLI’s Brain Quantitative Biomarkers

• Derives surface areas, thicknesses, and volumes

Measurements • Measurements are compared to diseased and

healthy populations.

Volumetric Measurements Surface Measurements T1-Weighted Image


79 year old healthy

male HLI screening

client.

Unique DWI imaging

overlay enables easy

visualization of enlarged lymph

nodes worrisome for

Lymphoma.

Subsequent biopsy

confirmed follicular

lymphoma.

Provisional Patent

Based on MRI-DWI normalization & PET-

CT like overlays

Non-contrast Radiation-free Dx

Visualization tool for cancer screening

Technology Case Study

CONFIDENTIAL - NOT FOR DISTRIBUTION 33 Siemens Liver Lab

Liver fat biomarker for metabolic syndrome/Diabetes type 2


Siemens compressed sensing segmented CINE WIP with peripheral gating: 7 minute non-contrast cardiac

MRI protocol from start to finish

Cardiac MRI for Structure/Function: Left ventricular Function


AI Driven Risk Prediction: Multimodal approach


Dementia Risk Prediction and Prevention


Precision Health Clinical Reports and Digital Experience:

Personalized data-driven analytics that enable risk reduction

Interactive, Customer-Centric User Experience

Clinical report showcases integrated

Diagnostics with quantitative genomic,

clinical and imaging biomarkers


HLIQ Cardio: Multi-modal Disease Risk Prediction

& Risk Mitigation for coronary artery disease


Health Nucleus Network Program


Sequencing Cost

AI & Machine

Learning

Advanced

Imaging

Imagine a day when nobody has to suffer from

unnecessary and preventable disease …

*illustrative 2015 2018 2020 2025 2030

WGS $4,000 $2,500 $1000 $400 $200

MRI $2,000 $700 $200 $100 $75

CT $350 $150 $50 $25 $50

Labs $200 $100 $80 $50 $25

Other $3,000 $2,000 $0 $0 $0

Total $12,000 $5,000 $1,600 $575 $350

Market Billionaire Millionaire Mainstream Birthright

Industry Trends

Precision Health is Coming


• Scheduling

• MRI Imaging

• CT Imaging

• Imaging interpretation

• Blood Work

• WGS sequencing & report

• Pharmacogenomics

• GWAS scores

• Training of MDs, MRI techs

• Genetic counselors

• Client Relationship and

Acquisition

• Placing Orders

• Consent

• Past Medical History

• Results Delivery

IMAGING CONCIERGE/

ORDERING

MD’s

…powered by

Hospital or Clinic role Imaging Center Role

HLI’s Role

• Traits and ancestry

• Imaging biomarkers

• Integrated reports

• Machine learning diagnostics

• Oversee IRB

Expanding Platform via Partnerships

Partners that can provide a sleek/modern precision health

experience

SITE RENDERING ENTRANCE

RECEPTION

PATIENT ROOMS

MRI ROOM


Providing precision health services at retail clinics has the potential to guide decision support and inform care pathways in a mainstream way

Enable retail clinics with

precision health analytic tools to

provide improved access to

preventative care


Medicine has been a clinical science,

supported by data.

Medicine is about to become a data science,

supported by clinicians.

Documents

Virtual Health Nucleus A scalable, multimodal, …...David S. Karow, MD, PhD Chief of Radiogenomics and Interim CEO, Human Longevity, Inc. Associate Professor of Radiology, UC San