On the measurement and interpretation of birth defect associations in epidemiologic studies

Abstract

The extent of clustering of 2 or more defects in the same infant can be expressed as the ratio of the observed number of infants with the defects (O) over the expected number of such infants (E). The expected is usually derived from the product of population rates of individual defects. Because large O/E ratios are obtained for many defect combinations, it has been suggested that clustering of defects is generalized and nonspecific. To control for the tendency of nonspecific clustering of defects, an alternative method is to perform the same calculations among multimalformed infants only. A main limitation of this method is that it adjusts for the clustering tendency of all defects rather than the ones of interest, often resulting in spuriously low O/E ratios. We present a new method to adjust for the tendency for nonspecific clustering between defects that overcomes this limitation. With this method, adjusted O/E ratios are inversely related to the proportion of infants who are multimalformed and have one or more of the defects being examined. Using data from the Metropolitan Atlanta Congenital Defects Program, we apply this method to the previously described associations among VACTERL defects and midline or "schisis" defects. We show that adjusted O/E ratios obtained are greater than those obtained by using multimalformed infants. For midline defects, many of the adjusted ratios were close to one, indicating nonspecific clustering of these defects. Finally, using the example of isotretinoin embryopathy, we show that O/E ratios depend highly on the frequency of exposure in the population, and thus, they should be interpreted with caution.

Epidemiological analysis of the schisis association in the Spanish registry of congenital malformations

“…The results of the analysis of the observed associations using the adjusted ratio between observed (O) and expected (E) values, applying the method of Khoury et al [1990], are presented in Table VIII. The analysis was done using the total number of cases with at least one of the schisis defects in children with and without blastogenetic defects and in the total number of malformed infants.…”

“…We analyzed the preferential association of schisis defects on the total number of malformed infants, using the method proposed by Khoury et al [1990]. In addition, we also separated the cases between those with and without blastogenetic defects (Table VIII), since two of the four schisis defects studied are of blastogenetic origin (NTD and DH), while the other two may not be (oral clefts and OM).…”

“…However, combinations of two or more schisis-type defects among infants with other nonschisis defects, as well as the significant preferential association between schisis defects of blastogenetic origin (such as EN, SB, and DH) and of nonblastogenetic origin (such as OM and CL), may be due to a chromosomal Khoury et al, 1990) Children with at least one blastogenetic defect abnormality, a single gene defect, or a long-term environmental agent. The high proportion of combinations involving oral clefts further supports this suggestion since, as pointed out by Czeizel [1981] affected sibs were only observed among index patients with the association of NTD and oral clefts.…”

“…To study the preferential association of different schisis defects, we used the adjusted ratio between observed (O) and expected (E) values, by applying the method proposed by Khoury et al [1990], which controls the nonspecific tendency of defects to cluster among themselves. The analysis was done separately on infants with blastogenetic defects [Opitz, 1993], on those without blastogenetic defects, and on the sum of these two groups.…”

Associated anomalies in individuals with polydactyly

“…The strength of the association between polydactyly and another congenital anomaly in the same infant was measured through observed/expected ratios, with expected values obtained by the adjusted method described by Khoury et al [1990]. The number of cases with a given anomaly diad (a given pair of defects either present alone or together with other anomalies in the same infant) was compared with their random expected number, derived from all infants having at least one of the defects involved in the diad within the total set of multiple malformed babies.…”