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, aka “precision” medicine, can be defined as an approach to medicine in which medical decisions are tailored to the individual patient. In theory, in patients with established disease, personalized medicine will make health care more efficacious, more affordable, and safer by avoiding costly and prolonged trial-and-error approaches, unwanted therapeutic side effects, and diminished treatment efficacy. In preclinical settings where an individual’s molecular profile could be used to estimate their risk of disease, precision medicine can be used to triage patients for more vigilant screening to identify disease presence before clinical indications and symptoms appear or to initiate preventative therapies. 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 benefits, 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 Chapter 7). Many of these modalities are already being used as biomarkers in a personalized medicine context, and all have the potential to do so. In this chapter we review the foundations of personalized pulmonary medicine and the current approaches being used to develop personalized diagnostic and treatment strategies for pulmonary disorders, 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 ...