The study included 910 case and 939 control probands (including some controls for cases later found to be ineligible). Among these 1,849 subjects, 531 could not be interviewed for family history because they were deceased (n = 294), lost to follow-up (n = 133), too ill or disabled (n = 101), or did not know their biological relatives (n = 3). Thirty-four percent (446/1,318) of remaining subjects were interviewed. Participation rates were higher in cases vs controls (37% [220/593] vs 31% [226/725], p = 0.024), women vs men (38% vs 29%, p = 0.001), and subjects aged ≥50 years vs <50 years (41% vs 28%, p < 0.001). Among the cases, participation rates did not differ significantly between subjects with epilepsy vs isolated unprovoked seizure, but were higher in subjects with onset at ≥20 vs <20 years (47% vs 34%, p = 0.004), or focal vs generalized epilepsy (45% vs 32%, p = 0.031).
In the cases (where relatives were identified for both interviewed and noninterviewed individuals), participation rates did not differ between those with and without a family history of epilepsy, based on review of the relatives' medical records (37.6% vs 38.2%, p = 0.92). Also, in the relatives of interviewed controls, the incidence rate of epilepsy, as determined from review of the relatives' medical records, was very similar to the incidence rate in the general population (standardized incidence ratio, adjusted for age, sex, and secular period = 0.99, 95% confidence interval 0.45–1.88). These analyses argue against selection bias related to family history in either cases or controls.
The 446 interviewed probands provided information for 2,936 first-degree relatives. For some of these relatives, medical record review was impossible: 774 had no contact with a REP provider; 1,294 were last seen by a REP provider ≥1 year before the proband interview and thus could subsequently have had seizures that were not documented in the REP records; and 44 either denied permission for research review or had uninformative records. Among the remaining relatives, 726 were presumed to be seizure-free, because they either had no REP diagnosis codes suggestive of seizures or were determined to be seizure-free on record review. Ninety-eight relatives had medical record–documented seizures. Two were excluded because seizure onset was after the family history interview was completed, leaving 96 affected relatives for analysis.
shows the distribution of positive responses by probands to specific questions in the screening interview, according to the relatives' medical record–based diagnoses. Sensitivity of the family history data was 62% (32/52) for relatives with epilepsy, but lower for those with isolated unprovoked seizures (50%), febrile seizures (56%), or other acute symptomatic seizures (21%). Among the relatives presumed to be seizure-free, only 2% screened positive.
Number (%) of relatives for whom proband responded positively to specific questions in family history interview, by medical record–based diagnosis of relatives
Among relatives with medical record–documented epilepsy, the proportion who screened positive was 90% in offspring, 80% in siblings, and only 32% in parents (p = 0.002, ). Similarly, among relatives with febrile seizures, the proportion who screened positive was 80% in offspring but lower in siblings (56%) and parents (0). Among relatives presumed to be seizure-free, the proportion who screened positive (false-positives) was greater for parents (4.6%) than siblings (1.6%) or offspring (1.3%).
Proportion of relatives for whom probands gave a positive response to any screen question, by medical record–based diagnosis of relatives and relationship to proband
For relatives with epilepsy, we examined sensitivity according to attributes of the probands and relatives (). Sensitivity did not differ between case and control probands or according to proband education. However, sensitivity was significantly greater for female vs male probands (74% vs 43%), and for probands aged <50 vs ≥50 years at the time of interview (78% vs 48%). Among case probands, sensitivity was unrelated to probands' age at first unprovoked seizure or epilepsy type, but was greater for probands with vs without a history of convulsive seizures (65% vs 14%).
Proportion of relatives with epilepsy for whom proband gave a positive response to any screen question, by proband and relative characteristics
Sensitivity was greater for relatives whose first seizure occurred at age <20 vs ≥20 years (81% vs 40%), for relatives with idiopathic generalized epilepsy (IGE) vs other epilepsy types (91% vs 54%), and, although not significantly, for relatives aged <40 years (100%) vs ≥40 years (59%), or deceased (36%) at the time of proband interview.
Given the markedly higher sensitivity for siblings and offspring than for parents, we examined the potential for confounding by relative type in the relations of sensitivity to the other variables. The distribution of relative types did not differ by proband case/control status, education, age at interview, or diagnostic features (epilepsy type, age at onset, or history of convulsive seizures). However, the proportion of affected relatives who were siblings or offspring was greater for female vs male probands (74% vs 33%), and for relatives aged <40 years vs ≥40 (100% vs 56%) years at interview, with onset <20 vs ≥20 years (73% vs 40%), or with IGE vs other epilepsy types (91% vs 49%). To control for potential confounding resulting from these differences, we examined the strongest predictors of sensitivity within strata defined by relationship to the proband (). Although power was limited by small sample size, the results generally confirmed those from the unstratified analyses. However, the difference in sensitivity between female and male probands was much diminished, suggesting it was largely due to confounding by relative type.
Proportion of relatives with medical record–documented epilepsy for whom probands gave a positive response to any screen question, stratified by relationship to proband