The primary care physician’s (PCP’s) decision framework and toolkit have evolved over the past two centuries. Diagnosis in the 19th century was driven by a patient’s history and physical examination. External cues interpreted by the physician’s senses served as input—the data was what the clinician could hear from the patient’s story, visualize, touch, smell, or even taste as was the case with tasting urine to diagnose diabetes.
The 20th century marked the addition of advanced diagnostic modalities such as laboratory testing, tissue analysis, and imaging that allowed physicians to interpret the body’s internal cues invisible to the naked eye. At times, this new medical technology led to the extinction of various parts of the history and physical examination, but more often it served as adjunct information.
The 21st century will be remembered as a time when genomic information became a key driver of clinical decisions. Although genomic information is also an internal cue invisible to the naked eye, it differs from traditional laboratory values and imaging. Genomic information is a permanent fingerprint that provides clues to historic and future states and insight into the pathophysiology of why the body reached a particular state, whereas laboratory values and imaging are snapshots of a patient’s state at a moment in time. Our hope is that use of genomic information might improve our ability to screen for disease, make accurate diagnoses, and allow for more appropriate therapies.
In this era of genomic-informed medicine, we will learn about new categories of diseases and mechanisms of disease that we did not previously know existed. Through genome sequencing technology, we can pool large populations of patients with similar symptoms and find genetic patterns, enabling us to discover novel disease-causing alleles and providing explanations for previously unexplained conditions. The genomic revolution promises to improve quality of care for patients and decrease cost for the healthcare system by driving more appropriate utilization of resources and decreasing adverse drug events. Adverse drug events and medication errors result in 700,000 emergency department visits, 120,000 hospitalizations, and $3.5 billion in medical costs. Even a modest decrease in adverse events would result in substantial savings.
The remainder of this chapter will help clinicians understand how we might apply genomic information in our clinical practices.
The Basics—Speaking the Language
Before we can discuss the clinical applications of genomics, let us review a few basic terms and concepts:
An organism’s complete set of DNA is called its genome. Virtually every single cell in the body contains a complete copy of the approximately 3 billion DNA base pairs that make up the human genome.
With its four-letter language, DNA contains the information needed to build the entire human body. A gene traditionally refers to the unit of DNA that carries the instructions for making a specific protein or set of proteins. Each of the estimated 20,000 protein coding genes in the human genome codes for an average of three proteins.
Located on 23 pairs of chromosomes packed into the nucleus of a human cell, genes direct the production of proteins with the assistance of enzymes and messenger molecules. Specifically, an enzyme copies the information in a gene’s DNA into a molecule called messenger ribonucleic acid RNA (mRNA). The mRNA travels out of the nucleus and into the cell’s cytoplasm, where the mRNA is read by a tiny molecular machine called a ribosome, and the information is used to link together small molecules called amino acids in the right order to form a specific protein.
Remarkably, over the human genome is more than 99% conserved, meaning that individuals differ in less than 1% of their genetic code.
Genetics is the study of a particular gene.
Genomics is the study of the function and interactions of the DNA in a genome. Genomics has a broader and more ambitious reach than genetics. Although more than 1800 single gene disorders have been identified, the study of genomics continues to hold great promise because new study techniques allow for the investigation of common multifactorial disorders caused by the interaction of genes and environment. Some of these interactions might confer a protective or pathologic role in the expression of these diseases.
Single-nucleotide polymorphism (SNP) is a variation of a single base pair on the DNA molecule. Scientists are studying how SNPs (pronounced as “snips”), in the human genome correlate with disease, drug response, and other phenotypes.
Genome-wide association studies (GWAS) are one type of research used in genomics to associate specific genetic variations with particular diseases. The method involves scanning the genomes from many different people and looking for genetic markers that can be used to predict the presence of a disease. Once such genetic markers are identified, they can be used to understand how genes contribute to the disease and develop better prevention and treatment strategies.
Personalized medicine is the tailoring of medical treatment to the individual characteristics of each patient. In order to do this, we classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventative or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.
Pharmacogenetics is the study of a person’s genetic makeup affecting the body’s response to drugs.
In the following section, we will list and demonstrate several concepts which PCPs will need to incorporate into clinical practice. To illustrate a typical PCP encounter, we will use fictional patient Jane Doe, a 38-year-old woman who presents to Dr. Smith’s office for a preventive care visit.
During medical training, many physicians hear “it’s all about the history.” As medicine advances into a new world influenced by genomics, a thorough family health history remains the cornerstone of an appropriate diagnosis and evaluation. Family health history continues to provide clinical utility as a proxy for genetic, environmental, and behavioral risk to health. It is critical to inform risk stratification, allowing for judicious use of screening and opening the door to early and even prophylactic treatment.
Despite its clear clinical utility, there is ample evidence that family health history is underutilized across the healthcare community, with most practitioners asking infrequently and inconsistently about their patients’ family health history. On average, PCPs spend less than 3 minutes collecting family health history. Given that one of the largest barriers to the collection of family health history is time, here are some existing solutions to this challenge:
Electronic family health history collection tools: A very useful example is the US Surgeon General tool, found at familyhistory.hhs.gov/
Use of ancillary staff to collect and obtain family health history information either by phone in advance or while the patient is waiting.
Office-based family health history questionnaires, which can be e-mailed or taken home. This approach requires careful thought on how to integrate the information gathered into the patient’s medical record.
During Ms. Doe’s preventive care visit, Dr. Smith obtains a complete family health history. He notes that her paternal aunt had breast cancer in her 40s. He also notes that she is of Ashkenazi Jewish ancestry.
The application of genomics is spreading from rare disorders to common conditions and patients are beginning to approach PCPs with questions about personalized medicine. Unfortunately, the primary care workforce has felt inadequate delivering genetic services and yet they must remain up to date with advances in genomics in order to recognize diseases with either a genetic etiology or implication for therapy. GWAS are rapidly discovering new genetic markers to predict disease on a weekly basis. The challenge is how to keep up with the rapid rate of genomic discoveries across the disease spectrum. Several online resources will help the PCP remain up to date. Point-of-care resources available through electronic health record systems or personal electronic applications will gain further development soon as well.