Whole Genome Sequencing and Machine Learning ... Title Whole Genome Sequencing and Machine Learning

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  • Whole Genome Sequencing and Machine Learning to Modernize AMR Diagnostics

    PACCARB – July 10, 2019

    JONG LEE, MBA DAY ZERO DIAGNOSTICS

    CEO & CO-FOUNDER

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 1

  • • Founded in 2016, spin-off from Kwon Lab at MGH

    • Based in Boston, MA

    • Developing sequencing- based diagnostic for AMR/S direct from clinical samples

    • Providing rapid sequencing based services for HAI outbreak control & hospital epidemiology

    Day Zero Corporate Overview

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 2

    Jong Lee, MBA CEO

    • Harvard & Harvard Business School

    • Experienced MedTech exec & consultant

    Doug Kwon, MD PhD CSO

    • Harvard & NYU

    Miriam Huntley, PhD CTO

    • MIT & Harvard • Expert in genomics, • Infectious Disease

    MD and Research Lab Director

    computational biology

  • Rapid vs. Comprehensive Tradeoff: DZD Will Deliver Both

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 3

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    Culture based methods gated by culture growth

    Sensor or PCR based methods limited to selected targets

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    Automated Culture

    Culture + PCR PCR / Molecular Probes

  • © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS

    Our Mission: Diagnose Infections on Day Zero

    6 Hours

    COMPANY CONFIDENTIAL 4

    Clinical Samples (e.g., Whole Blood)

    Species ID & AMR/S Profiles

  • Technology Required to Enable Clinical Use

    Whole Genome Sequencing

    Blood2Bac™ Sample Prep

    COMPANY CONFIDENTIAL © COPYRIGHT 2018 DAY ZERO DIAGNOSTICS 5

    Keynome® Algorithm

    MicrohmDB®

  • At 1 CFU/mL, must solve:

    1. Relative abundance: human DNA outnumbers bacterial DNA by 8-9 orders of magnitude

    2. Absolute abundance: there is only 10’s of femtograms of bacterial DNA

    3. Amplification inhibitors: Blood and blood collection containers carry amplification inhibitors

    Major Challenges to Culture-Free Pathogen Sequencing from Clinical Blood

    Required Host DNA/Cellular Reduction

    COMPANY CONFIDENTIAL 6© COPYRIGHT 2019 DAY ZERO DIAGNOSTICS

  • Blood2Bac: Agnostic Detection of Bacteria in Blood Down to 1 cfu/ml

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 7

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    P e r c e n t G e n o m e C o v e r e d

    Ratio of bacterial DNA / human DNA reads from 1 CFU

    Genome coverage achieved

    Target

  • SEQUENCING COST PER MB OF DATA DROPPING DRAMATICALLY

    NEW GENERATIONS ENABLE RAPID, SINGLE SAMPLE SEQUENCING

    Thesis: Sequencing Will Be A Diagnostic Utility

    COMPANY CONFIDENTIAL © COPYRIGHT 2017 DAY ZERO DIAGNOSTICS 8

    $0.01

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    $1,000.00

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    2001 2004 2007 2009 2012 2015

  • WGS Potential to be Highly Comprehensive vs. Biomarker Approach

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 9

    Top 5 Species: 60%

    WGS Potential: 100% Bacterial Species Abundance in Blood Cultures

  • Traditional AMR Prediction: Resistance Gene Lookup

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 10

    S. aureus + methicillin K. pneumoniae + cefazolin

    • Highly interpretable, backed by scientific understanding

    • Limited to a small subset of validated resistance genes – Not all mechanisms of resistance

    are well characterized or known – Complex mechanisms difficult to

    characterize with presence / absence of genes

    • Not comprehensive enough to predict susceptibility

    WGS data from Earle, S. G., et al. (2016). Nature microbiology, 1, 16041. Spades + BLAST of ArgANNOT resistance genes

    Percent of Isolates Containing Relevant AMR Genes

  • Keynome Accuracy Improves With Amount of Training Data in MicrohmDB

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 11

    • Keynome performance improves with data • Performance curves differ between

    species/drug combinations

  • MicrohmDB: Large Scale Dataset of Pathogen Genomes and AMR Profiles

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 12

    45,000 samples collected to date from multiple hospital microbiology labs

    High throughput whole genome sequencing (NextSeq, HiSeq) – 25,000 thus far

    Link genomes with phenotypic AMR data Bioinformatic annotations

    Collect Clinical Isolates Sequence Genomes Link AMR Data

  • DZD Vision: WGS Diagnostics Enable Large Scale Data Opportunity

    COMPANY CONFIDENTIAL © COPYRIGHT 2019 DAY ZERO DIAGNOSTICS 13

    GENOMIC DATA

    Hospital Outbreak Investigation MicrohmDB

    Epidemiology

    Antibiotic Target Discovery

    Whole Genome Sequencing and Machine Learning to Modernize AMR Diagnostics��PACCARB – July 10, 2019� Day Zero Corporate Overview Rapid vs. Comprehensive Tradeoff:�DZD Will Deliver Both Our Mission: Diagnose Infections on Day Zero Technology Required to Enable Clinical Use Major Challenges to �Culture-Free Pathogen Sequencing from Clinical Blood Blood2Bac: Agnostic Detection of �Bacteria in Blood Down to 1 cfu/ml Thesis: Sequencing Will Be A Diagnostic Utility WGS Potential to be Highly Comprehensive vs. �Biomarker Approach Traditional AMR Prediction: Resistance Gene Lookup Keynome Accuracy Improves With Amount of �Training Data in MicrohmDB MicrohmDB: Large Scale Dataset of �Pathogen Genomes and AMR Profiles DZD Vision: WGS Diagnostics �Enable Large Scale Data Opportunity