Leaders in Pharmaceutical Business Intelligence (LPBI) Group

LIVE — April 23, 1:55PM – CLINICAL UTILITY OF GENOME VARIATION  @ Cambridge HealthTech Institute’s 14th Annual Meeting BioIT World – Conference & Expo ’15, April 21 – 23, 2015 @Seaport World Trade Center, Boston, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

Dr. Aviva Lev-Ari will be in attendance on April 21, 22, 23

 

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CLINICAL UTILITY OF GENOME VARIATION 

1:55 Chairperson’s Remarks

Louis Fiore, M.D., MPH, Executive Director, MAVERIC, Research, Veterans Affairs Boston Healthcare System

450,000 Veterans DNA Sequenced on Illimina Chip customized with PTSD information at Veterans Affairs Boston Healthcare System, all SNPs recorded

CANCELLED — 2:00 Striking the Right Balance in Clinical Interpretation of Genomes

Elizabeth Worthey, Ph.D., Assistant Professor, Pediatrics; Director, Genomic Informatics, Human and Molecular Genetics Center, Medical College Wisconsin

I provide a review of the 2014 lessons learned in our molecular diagnostic lab and the challenges and opportunities for 2015. It focuses on the end-to-end solution for clinical genomics we have implemented, including platforms developed for genomic medicine clinical decision support. It also discusses how we integrate this data into the practice of medicine in our genomic medicine clinics, providing specific case examples.

2:30 Epigenetic Profiling of DNA Methylation to Identify Breast Tumor Aggressiveness

Adam Marsh, Ph.D., Professor, Center for Bioinformatics and Computational Biology, University of Delaware; CSO, Genome Profiling, LLC

Women with triple-negative genotypes (i.e., normal for the three common marker mutations for breast cancer) are still at risk for developing aggressive breast tumors. We identify a suite of differentially methylated CpG sites between normal and tumor breast tissues using NGS that indicate a high degree of epigenetic conservation among different triple-negative patients who have developed advanced-stage breast tumors. Subtle epigenetic shifts in methylation status may provide a key line of evidence for assessing tumor risk and informing therapy decisions between surgery or versus noninvasive treatments.

LIVE

How the Polar environment affect low metabolism (cold adaptation), epigenetics and tumor aggresivity in Breast Cancer

1. Clinical Utility of Genome Variation

• Human vs Monkey
• Human vs Human
• Intra – Human variation

1. Epigenetic DNA Methylation: Phynotype diversity

• Human Genome (Cytosine methylation)
• Intra-individual variation

Epigenetic Profiling Platform

• Triple Negative Breast Cancer (TNBC)
• Negative on HER-2
• Negative on Estrogen Receptor (ER)
• Negative on Progesteron Receptor (PR)

5mC: Unique Quantification Metrics

• Gardient MET score
• Mixed state CpG

Analytic Comparison of methylation States

Unique Gene Scoring Strategy

Comparative Changes for functional

Blood Study – NGS gDNA Method Comparison

1. Parkinson Samples
2. Methylation Profile: Bisulfitet Oxidation vs GenPro Prep
3. 3 early-onset Parkinson
4. 3 Normal population
5. Coriell BioBnk’Yale: preparation sequencing
6. Cornell: Epigenomics
7. Comparison of Mean Methylation by two Methods: GenPro and …..

Potential Epigenetic Blood Biomarkers: Parkinson vs Normal – DNA Methylation Patterns — different

TOP 10 KEGG Groups Parkinson vs Normal

• lymphocytes
• Neurodegenerative

Tumor Study  – Breast Tumor Profiling – Normal tissue vs Tumor Tissue – CpG SItes: Methylation gain, loss and no change = the majority

COMBINED PATIENT/SSAMPLE ANALYSES – TISSUE RESPONSE ACROSS PATIENTS

• Genome Profiling: COMPARISONS ACROSS GENES AND PATHWAYS
• Validation

Conclusions

In TNBC tumors – mapping methylation changes back to functional genes reveals large variation

SIgnificance

• 8%-10 of masectomies are therapeutically necessary — but only via post-op pathology
• Over diagnosis of Breast Cancer, ERplus

3:00 Establishing Clinical-Grade RNA Sequencing

Sheng Li, Ph.D., Instructor, Bioinformatics, Neurological Surgery, Weill Cornell Medical College

High-throughput sequencing drastically expands the potential for large-scale whole transcriptome profiling of clinical samples for disease monitoring and diagnosis. Here we established standard approach and analysis methods and benchmark datasets for evaluation of RNA-seq performance of different platforms, protocols and various qualities of input materials.

LIVE

Establishing Clinical-Grade RNA Sequencing – RNA and DIagnosis DIsease

• HIV RNA Test
• AlloMap — rejection of Heart transplantation
• oncoTypeDX — one single assay
• SOurce of the wiggles – Fetal Hypothulmus

INTEGRITY OF RNA SAMPLES – depends on many factors

• aldorithms for alignment and assembly
• rna fragmentation
• technology bifurcation

NEED for RNA Standards

Phase 1: Inter-Performance: Error highly variable amonf platform and daligners

• Samples A: Stragene vs Sample B
• Asso of biomolecular Research Facilities – NGS Study
• Nature Biotechnology and FDA Sequencing Quality Control (SeQC) COnsortium
• Roche
• Illimina — MOST RELIABLE for Isoforms
• Ion Torrent
• Pacific BioSciences –
  • highesr base efficient of junction detection efficiency is the highest for Pacific BioSciences

Inter-platform differential gene expression show 88%-97% agreement

Phase II InterProtocol  of Illumina 

Gene regions distribution varies betweenprotocols

• Intergenic
• Exon
• Mean FPKM differences

HIGH EXPRESSOR: PolyA and RING – PolyA is higher

Phase III: Degraded RNA

Full length genebodt coverage varied between preparation methods

Illumina Ribo-depletion protocol: Degraded RNA

SUMMARY

Inter-platform performance

Consortia: NIST, ABRF, FDA, ENCODE – Standards set up for RNA Studies

3:30 The Department of Veterans Affairs Precision Oncology Program: The Crossroads of Clinical Care and Research

Louis Fiore, M.D., MPH, Executive Director, MAVERIC, Research, Veterans Affairs Boston Healthcare System

This presentation describes a model for creation of “Learning Healthcare Systems” through integration of a clinical precision oncology program with a tailored research program that leverages and augments the clinical investment. Databases and applications that support clinical trial matching, capture of patient reported outcomes, clinician collaboration and patient outcome prediction will be discussed.

LIVE

MAVERIC – founded in 1997 120 person VA System for 150 Hospitals – SINGLE PAYER (VA Ssytem)

• Clinical – MDs
• Hospital Adm
• Clinical Research
• Pharma

INTEGRATING EMR WITH CLINICAL OUTCOME

• Point of Care
• OMICS data at VA – at the POC – Actionable Results
• Precision Medicine in the VA

1. 350,000 enrolled for DNA Sequencing – Million Veteran

LUNG CANCER @ VA – What mutation is the driver – Sequence Tumor

PRECISION ONCOLOGY

Target genes for sequencing

Lung Adenocarcinoma – Clinical NSCLC Cases – 724 consecutive FFPE

• UCSF designed Sequence data Tumor mutation, treatments, Outcomes in Knowledge Repository match to Clinical Trial.gov
• application of the Process for Lung Cancer to other indications
• Prediction regression inform Clinician – Stanford Medical Center engine

4:00 Conference Adjourns