Feasibility of identifying families for genetic studies of birth defects using the National Health Interview Survey

During the past decade, there has been significant progress in identifying the genetic basis of many Mendelian conditions. In February 2003, the Online Mendelian Inheritance in Man catalog reported the localization of 14,206 gene loci, of which 13,311 are autosomal, 792 are X-linked, and 103 are Y-linked or mitochondrial[1]. Some of these have been shown to cause birth defects (i.e., hypohidrotic ectodermal dysplasia, dentinogenesis imperfecta II, Papillon-Lefevre syndrome, Apert syndrome, aniredia, Van der Woude syndrome, popliteal pterygium, and congenital fibrosis of the extraocular muscles). Progress, however, has been substantially slower for the more common disorders that are complex and influenced by multiple genes interacting with each other and with environmental factors. For example, the search for the genetic basis of non-syndromic cleft lip with or without cleft palate (CL/P) began more than 60 years ago (see the classic work of Fogh-Andersen[2]), but despite a relatively high heritability rate for clefts[3], the search for susceptibility genes has only yielded weak linkages and inconsistent results [4‐6]. This may be due, in part, to the limitations of current linkage strategies as well as our lack of understanding of the role of genetic polymorphisms in response to environmental factors.

Several approaches (ie, linkage analysis, association studies) can be used to identify disease causing or disease predisposing genes [7, 8]. Most of them require, or their statistical power greatly benefits from, the use of "multiplex" families (families with two or more affected members). While birth defects surveillance systems are adequate at identifying individual cases, they rarely collect family history. The objective of this study is to determine the utility of the National Health Interview Survey to identify informative families for genetic studies of birth defects.

Table 1 shows the number and type of conditions found in the four groups of households. Of a total of 28,094 households surveyed for birth defects and impairments, there were 1,083 single non-familial, 55 multiple non-familial (total of 115 affected individuals), 54 single familial (total of 113 affected individuals), and 8 multiple familial (total of 16 affected people) households. Close to 60 percent of all birth defects in these groups were of the musculoskeletal system, such as musculoskeletal deformities of the skull, face, and jaw (including the sternocleidomastoid muscle); chondrodystrophy; osteodystrophies; congenital scoliosis; clubfoot; and flat foot/congenital fallen arches. The other most common conditions were congenital heart defects (CHD), spina bifida and hydrocephalus, and oral clefts. CHDs were particularly frequent in the multiple familial and in the single non-familial groups (26.9% and 20.8% of all the congenital anomalies in each group, respectively).

Table 2 presents individual and household characteristics of the four groups. No statistically significant differences were found; however, there was a higher percentage of females (68.7%, odds ratio [OR]: 1.8, 95% confidence interval [CI]: 0.7–5.1), of African-Americans (25.0%, OR: 2.8, 95% CI: 0.9–9.0), and of households with lower socio-economic status (<$20,000; 37.5%, OR:1.8, 95% CI: 0.5–6.9) in the multiple familial group. Also, none of the 8 households in this group was located in western states.

Table 3 details the number of households with at least one resident with a birth defect and shows projections for the total number of these households in the United States and by region using the 2000 U.S. Census report. Western states have the highest rate of households including residents with birth defects in two of the four groups, single non-familial and single familial.

Of the 54 households with single familial cases, 39 had two and 5 had three family members with the same condition. One household included a pair of male twins with 47, XYY karyotype. In the remaining 10 households, the affected family members had different types of birth defects (Table 5).

The objective of this study was to determine whether the National Health Interview Survey is useful in identifying households with families who are informative in the genetic study of birth defects. We used the Survey to estimate the total number of households where these families live by geographical region. It was thought that this information could be used by genetic researchers to target areas where the likelihood of finding these families is greater and to anticipate the needed resources with a better understanding of the scope of the task. Unfortunately, the results indicate that the NHIS provide limited useful information to be used in this manner.

We used the Survey, particularly years 1994/1995, because it presented several advantages. The NHIS is a large, representative sample of all U.S. households with an annual response rate greater than 90 percent[13]. These data are collected through a personal household interview conducted by interviewers employed and trained by the U.S. Bureau of the Census according to procedures specified by the National Center of Health Statistics and allows for the identification of households where one or more individuals with birth defects reside and the identification of individuals who have one or more than one birth defect. Furthermore, the addition of the Disability supplement in 1994/1995 resulted in specific birth defects on the condition lists unlike other versions of the survey. These data may also be used to identify various health problems, determine barriers to accessing and using appropriate health care, and to evaluate Federal health programs.

Several limitations of the NHIS might have conspired against its usefulness for the stated objective. The accuracy of the birth defect information has not been validated, there are no objective measurements since data are self-reported or by proxy and isolated conditions can not be studied, since most birth defects are grouped by organ of affection. Also, since many of the questions in the NHIS are predicated on limitation of daily activities, identification of cases is problematic as birth defects cause a range of limitations.

Issues around sampling also limit the usefulness of the NHIS in identifying informative families for genetic studies. Estimates are based on a sample of the population, thus are subject to sampling errors and the information on place of residence is limited to multi-state regions and not available at local levels such as states, counties, or districts. Also, since households were asked to identify conditions from specific grouped lists, we likely only identify families with two or more individuals with birth defects of the same class. Finally, several segments of the population are not included in the sample, such as patients in long-term care facilities, persons on active duty with the Armed Forces (though their dependents are included), and U.S. nationals living in foreign countries.

The difficulty to locate multiplex families using the NHIS suggests that population based ascertainment of families with two or more members with the same birth defect is an unrealistic strategy. Alternative strategies are needed to study the genetic contribution to most birth defects. One such strategy is to identify prospective participants in specialty clinics. Another excellent source of data, albeit much more expensive than ascertainment through clinics, are the large, collaborative, multi-state or nationwide studies of birth defects, such as the National Birth Defects Prevention Study [14, 15]. In addition to identifying families of interest, these studies collect extensive epidemiological data and DNA samples from which genetic susceptibility and gene-environment interactions can be studied.