Search

The Evaluation of Genomic Applications in Practice and Prevention Working Group was first convened in 2005 to develop and test evidence-based methods for the evaluation of genomic tests in transition from research to clinical and public health practice. Over the ensuing years, the Working Group has met 26 times, publishing eight recommendation statements, two methods papers, and one outcomes paper, as well as planning and serving as technical experts on numerous associated systematic reviews. Evaluation of Genomic Applications in Practice and Prevention methods have evolved to address implications of the proliferation of genome-wide association studies and are currently expanding to face challenges expected from clinical implementation of whole-genome sequencing tests. In this article, we review the work of the Evaluation of Genomic Applications in Practice and Prevention Working Group over the first 8 years of its existence with an emphasis on lessons learned throughout the process. It is hoped that in addition to the published methods of the Working Group, the lessons we have learned along the way will be informative to others who are producers and consumers of evidence-based guidelines in the field of genomic medicine.

All pregnant women should be screened for thyroid deficiency. Researchers measured the level of thyroid hormones in blood samples taken from pregnant women up to 10 years prior. Sixty-two women had low levels, a condition called hypothyroidism. Compared to 124 women who had normal levels during pregnancy, the 7- to 9-year-old children of the women with hypothyroidism scored lower on 15 tests of intelligence, language, reading ability, school performance and visual-motor performance. Nineteen percent had IQ scores of 85 or less.

Down's syndrome may be detected by maternal blood tests during the first trimester of pregnancy. Tests for this form of mental retardation are usually performed in the second trimester. Researchers performed blood tests and fetal chromosomal analysis in 4,412 older pregnant women. Forty-eight of 61 fetuses affected by Down's syndrome were detected by blood testing before 14 weeks gestation. Blood tests for low levels of pregnancy-associated protein A and elevated serum human chorionic gonadotropin (hCG), along with maternal age, detected Down's syndrome in about 60% of cases.

Prenatal blood tests for Down's syndrome in the fetuses of older pregnant women may offer a basis for deciding which of these women need amniocentesis as a further screening method. Women over 35 are considered to be at a higher risk for having children with Down's, and many doctors recommend amniocentesis as a screening procedure. Amniocentesis can result in fetal complications or death. Blood samples were taken from 5,385 pregnant women 35 years of age or older. These samples were analyzed for alpha-fetoprotein, estriol and human chorionic gonadotropin content, all thought to be associated with Down's syndrome in certain levels. The rate of detection of Down's syndrome reached as high as 89%, with a 25% false positive rate. Because of the risk of fetal loss with amniocentesis and the high cost of the test, the use of blood analysis as a screen for possible amniocentesis could save lives and money.

Exposure to environmental tobacco smoke may aggravate symptoms of asthma in children. Asthma is a chronic lung disease characterized by recurrent attacks of shortness of breath with wheezing. Among 199 children with asthma whose urinary levels of cotinine were measured, 116 reported no exposure to environmental tobacco smoke, 53 were exposed by their mother or other individuals and 30 were exposed by their mother and other individuals. Cotinine is a metabolic product of nicotine that is excreted in the urine. The average level of cotinine in the urine was 10 times higher in the children who were exposed to cigarette smoke by their mother and other individuals than in those who reported no exposure. Children exposed to cigarette smoke were more likely to experience severe symptoms of asthma than those not exposed.

Measuring three different biochemical markers after amniocentesis rather than one raised the level of detecting fetal Down's syndrome from 35% to 58%. Detection rate was slightly less for low risk mothers, 56%, than for high risk mothers, 60%. Amniotic fluid was evaluated for 962 women and adolescents in the second trimester of pregnancy. Fluid was tested for levels of chorionic gonadotropin (HCG) and estriol plus the usual serum alpha-fetoprotein. The concentration of HCG is two times greater than normal and unconjugated estriol levels 25% lower than normal in mothers pregnant with Down's syndrome babies. The reasons serum levels are different for Down's syndrome mothers are unknown.

It has been established that infants and children who are regularly exposed to tobacco smoke have more frequent and more serious respiratory illnesses than children not exposed to smoke. Children who are 'passive smokers' have usually been identified by obtaining information from the mother about the number of cigarettes smoked in the home, but it is now possible to measure environmental smoke exposure by testing the infant's urine for cotinine, a by-product of nicotine metabolism. These two techniques, interviewing the mother and testing for urine cotinine levels, were used and compared with each other in a study of 518 infants. The babies were six to eight weeks old and were having their first well-child visit with the doctor. Using a urine cotinine level of 10 micrograms per liter as a cut-off, the percentage of infants with a high level was calculated. Only 8 percent of the 305 infants from homes where no one smoked had high levels, whereas 96 percent from the 74 homes where the mother and one other family member smoked had high levels. If just the mother smoked, 91 percent of infants had high cotinine levels; if one family member smoked other than the mother, 44 percent of babies had high cotinine. Infants who were breast-fed by mothers who smoked had especially high urine cotinine, presumably because the breast milk of smokers contains large amounts of cotinine. The mother's estimate of how many cigarettes were smoked in the home correlated well with the urine cotinine level in the infant, suggesting that mothers are reliable sources for this information. Therefore, simply asking about family smoking habits can accurately identify infants at increased risk for respiratory diseases. (Consumer Summary produced by Reliance Medical Information, Inc.)

Cigarette smoking is known to contribute to coronary heart disease by altering blood lipids (fats). In adults, cigarette smoking causes an increase in total cholesterol, triglycerides, low (LDL) and very low density lipoproteins (VLDL), as well as decreases in high density lipoproteins (HDL) and apolipoproteins (the protein associated with HDL). Research indicates that low HDL and high LDL levels (a high LDL/HDL ratio) increase the risk for coronary artery disease. These alterations in blood lipids contribute to atherosclerosis, the narrowing of blood vessels, particularly those supplying the heart muscle. To see if these changes also occur in children, all available information on children between eight and 19 years old was reviewed. Children in this age group had 11.8 percent higher triglycerides, 12.4 percent higher VLDL, and 4.1 percent higher LDL. They also had 8.5 percent lower HDL and 3.7 lower total cholesterol. Although these results are similar to those found among smoking adults, except for the higher level of total cholesterol, the percentages were higher among children who smoked. Total cholesterol represents the net shift in the relationship of HDL and LDL and does not necessarily reflect adverse changes in lipoprotein levels. It is unclear whether children between eight and 19 who smoke, have an increased risk for coronary heart disease later in life. (Consumer Summary produced by Reliance Medical Information, Inc.)