A Pilot Project Exploring the Impact of Whole Genome Sequencing in Healthcare

Whole genome sequencing (WGS) and whole exome sequencing (WES) services are currently
available to and are being utilized by physicians and their patients in both research and
clinical settings. The widespread availability and use of WGS and WES in the practice of
clinical medicine is imminent. In the very near future, sequencing of individual genomes will
be inexpensive and ubiquitous, and patients will be looking to the medical establishment for
interpretations, insight and advice to improve their health. Developing standards and
procedures for the use of WGS information in clinical medicine is an urgent need, but there
are numerous obstacles related to integrity and storage of WGS data, interpretation and
responsible clinical integration. MedSeq™ seeks to develop a process to integrate WGS into
clinical medicine and explore the impact of doing so.

We believe that WGS will be used in many ways, including two distinct and complementary
situations. In generally healthy patients, physicians will use the results of WGS to derive
insight into future health risks and inform prevention and surveillance efforts, a category
we refer to as General Genomic Medicine. In patients presenting with a family history or
symptoms of a disease, physicians will use the results of WGS to interrogate particular sets
of genes known to be associated with the disease in question, a category we refer to as
Disease-Specific Genomic Medicine.

Beginning in fall 2012, we will enroll 10 primary care physicians and 100 of their healthy
middle-aged patients to evaluate the use of General Genomic Medicine, and 10 cardiologists
and 100 of their patients presenting with hypertrophic cardiomyopathy (HCM) or dilated
cardiomyopathy (DCM) to evaluate the use of Disease-Specific Genomic Medicine. We will
randomize physicians and their patients within each of the above models to receive clinically
meaningful information derived from WGS versus current standard of care without the use of
WGS.

MedSeq™ is comprised of three distinct but highly collaborative projects. Project 1 will
enroll physicians and patients into the protocol, educate the physicians on basic genomic
principles and safely monitor the use of genomic information in clinical practice. Project 2
will use a WGS analysis/interpretation pipeline to generate a genome report on each patient
randomized to receive WGS in this protocol. Project 3 will examine preferences and
motivations of physicians and patients enrolled, evaluate the flow and utilization of genomic
information within the clinical interactions, and assess understanding, behavior, medical
consequences and healthcare costs associated with the use of WGS in these models of medical
practice.

In an extension phase of the study, we will 1) recruit approximately 10-15
patient-participants who self-identify as African or African American, whose physicians deem
to be healthy. All will be placed in the whole genome-sequencing arm of the study. They will
undergo the same activities as traditional MedSeq participants except for randomization. 2)
We will conduct a targeted phenotype assessment on MedSeq Project patient-participants who
are identified to have a monogenic finding. We plan to perform additional analysis by
reviewing their medical records and looking specifically with their variant in mind to see if
features associated with the variants were known prior to the study or were identified by
further testing or by their physical during the course of the study.

This initiative will significantly accelerate the use of genomics in clinical medicine by
creating and safely testing novel methods for integrating information from WGS into
physicians' care of patients.

Note for Age Eligibility:

- Cardiology patients 18 Years to 90 Years OR

- Primary Care Patients 40 Years to 65 Years (Adult, Senior)

Inclusion Criteria:

Primary Care

- Generally healthy (as defined by the primary care provider) adult patients at Brigham
and Women's Hospital ages 40-65. All patients must be fluent in English.

Cardiology

- Patients in the Partners Healthcare System who are 18 years or older with a diagnosis
of hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) and a family
history of HCM or DCM who previously had or who are candidates for targeted HCM or DCM
genetic testing through routine clinical practice within Partners. All patients must
be fluent in English.

Exclusion Criteria:

Primary Care

- Patients who do not meet the above criteria. Patients with cardiac disease or a
progressive debilitating illness. Patients who are pregnant or patients whose
spouses/significant others are pregnant. Patients with untreated clinical anxiety or
depression (as measured by a Hospital Anxiety and Depression Scale (HADS) score > 11
administered at the baseline study visit.)

Cardiology

- Patients who do not meet the above criteria. Patients with a progressive debilitating
illness. Patients who are pregnant or patients whose spouses/significant others are
pregnant. Patients with untreated clinical anxiety or depression (as measured by a
Hospital Anxiety and Depression Scale (HADS) score > 11 administered at the baseline
study visit.)

Extension Phase - Additional Inclusion Criteria

Part 1:

- Above inclusion and exclusion criteria PLUS:

- Inclusion: Self-identify as African or African American.

Part 2:

Inclusion Criteria

- MedSeq participants determined to have a monogenic finding

Exclusion Criteria

- Participants not previously enrolled in MedSeq Project

- Participants not identified to have a monogenic finding