NCGENES

North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES). The goal of NCGENES is to learn if “next-generation sequencing”, is ready to be used in routine medical care. It will be used for a new genomic test called Whole Exome Sequencing (WES).

NCGENES is broad in both ambition and scope. However, any narrower focus would leave inadequately addressed the most pressing challenges that face widespread clinical implementation of WES, namely, assessing the diagnostic potential of genomic analysis in diverse contexts and dealing with return of results. The overall project is organized into three integrated and interdependent projects:

• Project 1: Clinical Genomic Study
• Project 2: Analysis and Interpretation of Sequencing Data
• Project 3: Ethical and Psychosocial Implications Research

Upon completion of this project we aim to have established an infrastructure by which to apply genomic sequencing for the tangible benefit of patients. We are optimistic that by addressing central challenges facing the clinical implementation of genome-scale analysis, we will contribute significantly to the establishment of best practices as medicine moves into the genomic era.

Overall Study Aims

Aim 1

Evaluate the use and performance of WES as a diagnostic tool. The most promising immediate clinical application of genome-scale sequencing is its potential for facilitating diagnosis. While discrete, highly penetrant genetic lesions are individually rare, they cumulatively represent a substantial burden of disease, and the application of WES in this subset of patients offers a powerful new diagnostic strategy to enhance their care. In this first Overarching Aim, this project will investigate the application and use of WES as a diagnostic tool. Project 1 will identify critical clinical characteristics that can guide its utility for diagnosis and assess how it influences patient care. Project 2 will assess performance characteristics of WES and integrate it within the context of an active clinical laboratory. Project 3 will address perceptions, understanding, and impact of diagnostic WES information on patients and their family members.

Aim 2

Evaluate the occurrence, use and impact of incidental WES information. A central challenge which must be addressed if WES is to be successfully applied clinically is the inevitable generation of a great deal of incidental or “collateral” information. This proposal outlines a strategy by which clinicians, patients and the clinical laboratory can deal with a vast array of heterogeneous incidental information while both protecting patients and preserving their autonomy. Project 1 will assess how the generation of incidental information changes patient care and what types of incidental information patients elect to have returned. Project 2 will assess the nature and frequency of incidental information. Project 3 will develop materials to facilitate patient decision making regarding return of incidental findings and will assess factors associated with choosing to receive incidental information and how patients react to and share it.

Aim 3

Develop practical, ethical, and clinically-oriented mechanisms to facilitate interpretation, management, reporting and patient decision making about WES data. Another central challenge to clinically implementing WES is the large amount of information which will be generated. Therefore, in this third Overarching Aim, clinically oriented structures will be created and refined for the classification, storage and transmission of data to help patients and clinicians make sense of it. Project 1 will establish clinically relevant analytic schemes to categorize WES data. Project 2 will optimize strategies for managing and reporting WES data within this clinical structure, and Project 3 will evaluate the efficacy and evolution of the classification and reporting processes in order to provide grounds for empirically informed recommendations for future practice.

Aim 4

Apply WES in medically underserved groups to explore special opportunities and challenges to the broad implementation of clinical WES. As we stand on the cusp of genomic medicine, we must ensure that all have access to its benefits and avoid creating an unjust “genomic divide”. We will implement WES in medically underserved populations to identify special challenges and opportunities that exist within these communities. Project 1 will ensure the robust participation of underserved populations. Project 2 will address the frequency and nature of WES findings in these populations. Project 3 will identify barriers to recruitment and retention and will evaluate whether perceptions, use, knowledge and impact of WES data differ among these populations.