The challenge going forward is to screen populations, independent of family history and independent of clinical status, for variants relevant to health and disease and to apply this information to make risk assessments that can be used to improve the health care of an individual patient and his or her family.
The objective of population screening is to examine all members of a designated population, regardless of family history. Applying this information requires that we demonstrate that genetic risk factors are valid indicators of actual risk in an individual patient and, if they are valid, how useful such information is in guiding health care. Genetic screening is an important public health activity that will become more significant as more and better screening tests become available for determining genetic susceptibilities for disease.
Newborn Screening
The best-known population screening efforts in genetics are the government-supported or government-mandated programs that identify presymptomatic infants with diseases for which early treatment can prevent or at least ameliorate the consequences (Table 18-1). For newborn screening, the presence of disease is generally not assessed by determining the genotype directly. Instead, in most instances, asymptomatic newborns are screened for abnormalities in the level of various substances in the blood. Abnormalities in these metabolites trigger further evaluation to either confirm or rule out the presence of a disorder. Exceptions to this paradigm of using a biochemical measurement to detect a disease-causing genotype are screening programs for abnormalities in hearing, in which the phenotype itself is the target of screening and intervention (see later).
TABLE 18-1
Some Conditions for Which Newborn Screening Has Been Implemented
| Condition | Frequency (per 100,000 newborns)* |
| Congenital hearing loss | 200 |
| Sickle cell disease | 47 |
| Hypothyroidism | 28 |
| Phenylketonuria | 3 |
| Congenital adrenal hyperplasia | 2 |
| Severe combined immunodeficiency | 2 |
| Galactosemia | 2 |
| Maple syrup urine disease | ≤1 |
| Homocystinuria | ≤1 |
| Biotinidase deficiency | ≤1 |
Many of the general issues concerning genetic screening are highlighted by newborn screening programs. A determination of the appropriateness of newborn screening for any particular condition is based on a standard set of criteria involving clinical validity and clinical utility (see Box). The design of newborn screening tests includes keeping false-negative rates low so that true-positive cases are not missed, without making the test so nonspecific as to drive the false-positive rate unacceptably high. False-positive results cause unnecessary anxiety to the parents and also increase the costs, because more unaffected infants have to be recalled for retesting; at the other extreme, false-negative results vitiate the purpose of having a screening program. The criterion that the public health system infrastructure be capable of handling the care of affected newborns identified by screening is often underemphasized in discussions of the clinical utility of screening, but must also be considered in deciding whether to institute screening for any given condition.
The prototype condition that satisfies all of these criteria is phenylketonuria (see Chapter 12). For decades, finding elevated levels of phenylalanine in a spot of blood on filter paper obtained soon after birth has been the mainstay of neonatal screening for phenylketonuria and other forms of hyperphenylalaninemia in the United States, all the provinces of Canada, and nearly all developed countries. A positive screen result, followed by definitive confirmation of the diagnosis, led to the institution of dietary phenylalanine restriction early in infancy, thereby preventing irreversible intellectual disability.
General Criteria for an Effective Newborn Screening Program
