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Introduction

Since the first draft sequences of the human genome were completed in 2001,1,2 medical research has increasingly focused on the utilization of genetic and genomic profiling in the prediction of disease susceptibility and natural history, as well as drug response and drug development. Personalized medicine can be defined as an approach to medicine in which medical decisions are tailored to the individual patient. In theory, personalized medicine will avoid costly and prolonged trial and error approaches resulting in unwanted therapeutic side effects or diminished treatment efficacy. Diagnostically, personalized medicine uses molecular tracking to signal risk of disease on a genetic level, which may identify disease presence before clinical indications and symptoms appear. Thus, personalized medicine enhances the focus on preventive medicine at the primary, secondary, and tertiary levels. Fully realized, personalized medicine has the potential to facilitate early diagnosis and/or prevention of disease and selection of optimal therapeutic choices with minimal attendant side effects for established disease states. The potential savings, from both a financial and quality-of-life perspective, are enormous.

Much of the efforts to adopt personalized medicine into clinical practice have centered on genetic approaches, as sequence changes in deoxyribonucleic acid (DNA) have been closely associated with a wide range of disease susceptibilities and therapeutic responses. However, the “omics” era includes enhanced focus on cellular and metabolic changes downstream of DNA sequence variation including genomics or transcriptomics (the analysis of gene expression), proteomics (the analysis of protein changes), and metabolomics (the analysis of end products of cellular metabolism). Adding to genomic complexity are the so-called epigenetic changes, the study of changes in gene expression or cellular phenotype caused by mechanisms other than changes in DNA sequence, such as DNA methylation, post-translational modification of gene expression, and microRNA (see further in Chapter 7). Each of these genomic study types has the potential to serve as a biomarker in a personalized medicine context.

In this chapter, the foundations of personalized pulmonary medicine will be reviewed and current approaches designed to facilitate a personalized approach to the diagnosis and treatment of pulmonary disorders will be discussed, including specific examples of personalized approaches currently being implemented in clinical practice. We provide overviews of human genetics, personalized pulmonary diagnostic testing, pharmacogenomics, biomarkers, and future implementation as they relate to personalized respiratory medicine.

Determinants of the Clinical Utility of A Genetic Test

The predictive power of a genetic test is a function of four interdependent estimable parameters: (1) the heritability of the trait; (2) the penetrance of the tested genetic variant; (3) allelic heterogeneity; and (4) the variant allele frequency.

Heritability can be defined as the proportion of disease risk that is explained by genetic determinants. Heritability is highest (ã100%) among monogenic diseases like cystic fibrosis (CF), while common diseases such as asthma or obstructive sleep apnea have more modest estimates (30%–60%), with a substantial ...

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