ClinSeq: A Large-Scale Medical Sequencing Clinical Research Pilot Study

The purpose of ClinSeq is to pilot large-scale medical sequencing (LSMS) in a clinical

research setting. By conducting LSMS and returning individual results to participants, we
will investigate some of the technical, medical, and genetic counseling issues that accompany
the implementation of LSMS in the clinical setting.

A cohort of ~2,000 individuals selected from the surrounding general population is being
evaluated at the NIH Clinical Research Center (CRC) for a common set of cardiovascular
phenotypic features, including, but not limited to, coronary artery calcification, lipid
profiles, and blood pressure. During their initial visit, participants undergo a brief
clinical evaluation, and have blood samples collected for genomic analysis. Additionally,
they are asked to provide baseline information about pertinent health behavior and a family
history. During their initial visit and as the study progresses, participants may be asked to
complete surveys related to various socio-behavioral aspects of their participation, such as
their attitudes toward learning individual results or health behaviors related to receipt of
results.

Most participants have exome sequencing (ES), and selected participants will have genome
sequencing (GS). We have developed analytic algorithms to distinguish potentially pathogenic
genetic alterations from normal variation (Gonsalves et al., 2013; Johnston et al., 2012; Ng
et al., 2013) and will test for associations of genomic variants with a variety of
phenotypes. Sequence variants deemed clinically relevant are validated in a CLIA-certified
laboratory and the results offered to that subject. ClinSeq is designed to provide the
long-term potential for pursuing many different clinical projects.

Relatives of ClinSeq participants may be invited to enroll in the project for more

limited studies if their participation aids our understanding of the gene variants detected
in the

probands. For example, these relatives may undergo genetic testing for co-segregation of
known or suspected disease-causing variants, and/or phenotyping relevant to the disease in
question.

We aim to utilize the procedures and infrastructure we have developed for generating and
analyzing data to address some of the logistic,biomedical, and counseling challenges related
to LSMS.

- INCLUSION CRITERIA:

Group A

We plan to recruit a cohort whose risk to develop coronary artery disease will range from
less than 5 percent, based on the 10-year-risk provided by the Framingham risk score, to
greater than 10 percent, and including those with known coronary artery disease. The
10-year-risk will be measured by the Framingham risk score based on LDL cholesterol levels.

Individuals eligible for Bins 1-3 of this study will be 45 to 65 years of age, and
individuals eligible for Bin 4 must be 35-65 years of age. We selected this cutoff as we
are interested in recruiting a cohort whose coronary artery calcification (CAC)
measurements range from normal to diseased, and it has been shown that abnormal CAC is
infrequent below this age. Also, individuals eligible for this study will be required to
have a primary care physician or equivalent with whom we can communicate in the event we
uncover a condition that merits follow-up. The exception to this includes individuals in
Group A2 who are recruited through the community outreach being done by Ms. Sandra Epps.
These individuals will not be required to have a primary care physician, although we will
strongly recommend that they attend a community health clinic for follow-up on clinical
recommendations from the study. Additionally, individuals eligible for this study will be
required to be non-smokers at the time of enrollment, for our purposes defined as someone
who has not smoked regularly during the previous 12 months.

Due to the large number of individuals to be recruited and the intention to follow this
cohort longitudinally, we will focus our efforts on the metropolitan DC and Baltimore areas
(in order to minimize reluctance to participate because of travel limitations). If
recruitment is below anticipated levels, we may seek additional subjects from the Richmond,
VA metropolitan area. Individuals who are not local to these areas may be considered for
participation if they are part of other protocols within NHLBI, and travel to the NIH
Clinical Research Center on a regular basis for follow-up, or if they are willing to travel
to the NIH as needed for protocol participation (at their own expense). Bin 4 participants
will be eligible to have the cost of their transportation, meals and lodging covered if
they must travel >500 miles for their clinical visits.

An eligibility screen will be performed by telephone to ascertain age, basic demographics,
smoking history, and presence or absence of known cardiovascular disease. We intend to
recruit persons of both sexes, of diverse ethnic and racial categories, and from various
socio-economic backgrounds.

Group B

The eligibility for Group B is distinct from Group A. Group B eligibility requires:

1. relative enrolled in Group A

2. age over 18 years, unless the phenotype under study affects children

EXCLUSION CRITERIA:

Individual excluded from participating in the study include: (1) first-degree relatives of
enrolled ClinSeq participants (unless they fall into Group B); and (2) individuals who are
directly involved with gathering data and analyzing the clinical and genotyping data,
including the Principal Investigator, the Associate Investigators, the ClinSeq staff
involved with the subjects at the clinical level (such as the Nurse Practitioner, Genetic
counselor, etc.), and the staff at NISC involved with generating and analyzing the sequence
data ; and (3) individuals who request access to their raw sequence data for analysis
outside of ClinSeq ; and (4) individuals who are already enrolled in another study that
provides genome or exome sequencing, such as the GENE-FORECAST Study (14-HG-0048).