Constance M. Vadheim

A Prospective Study of the Development of Diabetes in Relatives of Patients with Insulin-Dependent Diabetes

BACKGROUND The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race. METHODS From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors. RESULTS Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes. CONCLUSIONS Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.

Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews

Genetic factors have been implicated in the etiology of inflammatory bowel disease (IBD) because of the increased occurrence of IBD in relatives. To further characterize the familial aggregation of IBD, we obtained family histories by interview on 188 IBD patients, including 154 Ashkenazi Jews (82%), ascertained through a Los Angeles gastroenterology practice. Thirty-three index cases (17.6%) had at least one affected first-degree relative; an additional 11 had more distant affected relatives. Thus, 23.4% of our sample had a positive family history. The quantification of empiric risk estimates for various classes of relatives has been quite limited and has been reported in only a few series. An important goal of our study was the determination of the specific empiric risk figures for relatives. We obtained uncorrected risk estimates of 2.5% to off-spring, 5.2% to siblings, and 2.9% to parents. Although the highest risk we observed is to siblings, IBD has a variable and often late age of onset, and it is likely that many relatives, particularly offspring, of patients in this sample have not reached the age at which they will manifest clinical disease. Thus, these uncorrected risks as well as those reported in the literature are an underestimate of the true empiric risks. To provide an estimate of the true lifetime risks, we utilized age-specific incidence data to calculate the following age-corrected empiric risk estimates for IBD: 8.9% to offspring, 8.8% to siblings, and 3.5% to parents. It is these latter age-corrected estimates that are most appropriate for both genetic counseling and genetic modeling.

Preferential Transmission of Diabetic Alleles within the HLA Gene Complex

Several studies suggest a higher incidence of insulin-dependent diabetes mellitus (IDDM) among the offspring of men with the disease than among those of female diabetics. Differential transmission by the father of genes that predispose to diabetes may explain this phenomenon. To test this hypothesis, we examined parent-to-offspring transmission of HLA haplotypes and DR (D-related) alleles in 107 nuclear families in which a child had IDDM. We observed that fathers with a DR4 allele were significantly more likely to transmit this allele to their diabetic or nondiabetic children than were mothers with a DR4 allele (72.1 vs. 55.6 percent, P less than 0.001). No differences between parents were observed for HLA-DR3; however, DR3 was transmitted significantly more than 50 percent of the time from either parent (P less than 0.001). These data suggest that differential parental transmission of the HLA-DR4-linked diabetes-predisposing allele may explain the higher risk of diabetes among children of diabetic fathers than among those of diabetic mothers. In addition, the excess transmission of diabetogenic HLA alleles from parent to offspring may explain how these deleterious genes continue to recur at such high frequencies in the general population.

Genetic Marker Associations With Proliferative Retinopathy in Persons Diagnosed With Diabetes Before 30 yr of age

It has been suggested that HLA-DR4 is a marker of genetic predisposition to proliferative retinopathy. To investigate this relationship and potential associations between other polymorphic genes and proliferative retinopathy, a sample (n = 428) of participants in the population-based Wisconsin Epidemiologic Study of Diabetic Retinopathy was selected for typing for HLA-A, -B, -C, and -DR and a panel of other polymorphic genes. The presence of proliferative retinopathy was determined from grading of stereoscopic color fundus photographs taken at 2 examinations, 4 yr apart. In logistic regression models with repeated measures, persons with HLA-DR4 who were negative for DR3 were five times more likely to have proliferative retinopathy than those negative for both antigens after adjusting for other potential risk factors (Odds ratio = 5.43, 95% Confidence Interval (Cl) = 1.04, 28.30). HLA-C2, AK-2, and MNSs-S also were associated positively with proliferative retinopathy, and HLA-DR8 was associated inversely with this complication of diabetes in each case before adjusting for the number of comparisons. These data suggest that the genetically determined immunopathic mechanisms leading to diabetes, and in linkage disequilibrium with DR4, may independently contribute to the development of proliferative retinopathy.

Epidemiology of diarrheal disease among children enrolled in four west coast health maintenance organizations

BACKGROUND We used information from the Vaccine Safety Datalink (VSD) about approximately 1 million children enrolled in four health maintenance organizations to assess the morbidity from diarrhea and estimate the disease burden of rotavirus. METHODS We examined trends of diarrhea-associated hospitalizations and emergency room (ER) visits among VSD children ages 1 month through 4 years during October, 1992, through September, 1994 (two rotavirus seasons) and estimated the morbidity from rotavirus on the basis of characteristic patterns of age and seasonality. RESULTS Overall diarrhea was associated with 6.3% of hospitalizations and 4% of ER visits. During a childs first 5 years of life, we estimated that 1 in 57 was hospitalized and 1 in 21 required an ER visit because of diarrhea. Each year the number of diarrhea-associated hospitalizations and ER visits was greatest in winter among children ages 4 to 23 months and peaked in November in California and during February in Oregon and Washington. The winter seasonality of diarrhea-associated hospitalizations reflected the trends for diarrhea of presumed noninfectious and viral etiologies, which together accounted for most (92.9%) hospitalizations. CONCLUSIONS Diarrhea is an important cause of morbidity among VSD children. The epidemiologic patterns of diarrhea-associated hospitalizations and ER visits resembled those reported previously for rotavirus diarrhea, suggesting that rotavirus may be a major contributor to the overall morbidity from diarrhea. Enhanced surveillance by screening for rotavirus in a sample of children with diarrhea will permit a more accurate assessment of the disease burden of this pathogen and the cost effectiveness of a rotavirus immunization program.

Comparative safety and immunogenicity of two recombinant hepatitis B vaccines given to infants at two, four and six months of age

OBJECTIVES To evaluate the relative safety and immunogenicity of the two recombinant hepatitis B vaccines licensed in the United States with doses recommended for routine immunization of low risk infants and a schedule that corresponds with routine pediatric visits. METHODS Healthy infants were immunized at 2, 4 and 6 months of age with hepatitis B vaccine manufactured by either SmithKline Beecham (Engerix-B, 10 micrograms/dose, n = 228) or Merck and Co. (Recombivax HB, 2.5 micrograms/dose, n = 200). Adverse reactions were ascertained by parental reports and interviews and by review of medical records. Antibody concentrations to hepatitis B surface antigen (anti-HBs) were measured in sequential serum specimens by enzyme immunoassay. RESULTS Adverse reactions were mild and the rates were not significantly different between the two groups. After the first and second doses the rates of seropositivity (> or = 10 mIU/ml) and seroprotection (> or = 10 mIU/ml) were significantly higher in infants given SmithKline Beecham vaccine (P < 0.01). After the second and third doses infants given SmithKline Beecham vaccine also had significantly higher geometric mean anti-HBs concentrations compared with those given Merck vaccine (348.0 mIU/ml vs. 66.9 and 1914.8 mIU/ml vs. 514.8 mIU/ml, respectively, P < 0.001). Nevertheless after the third dose 99% of infants in both vaccine groups achieved seroprotective antibody concentrations. CONCLUSIONS Both recombinant hepatitis B vaccines were safe and immunogenic when administered concurrently with other pediatric vaccines at 2, 4 and 6 months of age, but earlier protective responses were observed with the SmithKline Beecham vaccine than with the Merck vaccine.

INHERITED SUSCEPTIBILITY TO INSULIN-DEPENDENT DIABETES IS ASSOCIATED WITH HLA-DR1, WHILE DR5 IS PROTECTIVE

Of the HLA allelic associations with insulin-dependent diabetes (IDD) reported to date. DR3 and DR4 have been the most positive and DR2 the most negative. In 952 Caucasian proband patients reported here, only 57 or 6% had no DR3 or DR4 alleles. When these 57 patients were compared to 249 Caucasian controls similarly lacking DR3 and DR4 antigens, there were excesses of DR1 (P = 0.13) and DRW8 (P = 0.01) and deficiencies of DR2 (P = 0.03) and DR5 (P = 0.03) in the patient group. The most common phenotype in this group of patients was DR1/DR7 (12.3%). Only four DR-homozygous patients involving alleles other than DR3 and DR4 were found by genotyping, and all were DR1 homozygotes. Among 506 patients wuth DR3/DRX or DR4/DRX phenotypes, DR1 was more frequent (P = 0.001; Bonferronni P = 0.006), and DR2 (P = 0.001) and DR5 (P = 0.001) less frequent than 243 HLA-matched controls. Of 187 patients with a single DR3 and no DR4, DR1 was more frequent (P = 0.02), with DR2 (P = 0.001) and DR5 (P = 0.02) less frequent than 94 HLA DR-compatible controls. Among 319 patients with a single DR4 but no DR3, DR1 was again more frequent (P = 0.01) and DR2 (P = 0.001) and DR5 (P = 0.001) less frequent than 149 HLA-matched controls. We conclude that DR1 is an additional risk DR allele for IDD to that of DR3 and DR4, and DR5 an additional protective DR allele to that of DR2.

HLA-DR3 and DR4 and their relation to the incidence and progression of diabetic retinopathy.

PURPOSE Cross-sectional data from the Wisconsin Epidemiologic Study of Diabetic Retinopathy indicated that patients with HLA-DR4, but not DR3, were more likely to have prevalent proliferative retinopathy than those without both antigens. We describe the relation of HLA-DR3 and DR4 antigens to the 14-year incidence and progression of diabetic retinopathy and macular edema in this cohort. DESIGN A population-based cohort study. PARTICIPANTS A probability sample of male and female patients receiving primary care for diabetes in 11 counties of southern Wisconsin. METHODS Participants were invited for a baseline examination in 1980 to 1982, with follow-up examinations at 4, 10, and 14 years later. At the 4-year examination, a random sample of participants (n = 428) diagnosed with diabetes before the age of 30 and taking insulin were selected for HLA-DR typing. MAIN OUTCOME MEASURES Fourteen-year incidence and progression of diabetic retinopathy and macular edema based on masked stereoscopic fundus photographic grading. RESULTS There was no relation between HLA-DR3 and DR4 status with the 14-year incidence and progression of diabetic retinopathy, progression to proliferative retinopathy, and incidence of macular edema. Patients with either HLA-DR3 or DR4 were less likely to progress to proliferative retinopathy compared with those who were negative for both, although these relations were not statistically significant. The associations did not vary after adjusting for hypertension status, baseline retinopathy, and glycosylated hemoglobin levels, or after stratifying by duration of diabetes (less than 10 years vs. 10 years or more) and age at diagnosis of diabetes (less than 15 years vs. 15 years or more). Furthermore, 10-year mortality and 14-year nephropathy rates did not differ by HLA-DR3 or DR4 status, suggesting that selective mortality did not explain the pattern of associations seen. CONCLUSIONS In contrast to the initial cross-sectional findings, these data suggest that HLA-DR3 or DR4 status is unrelated to 14-year incidence and progression of diabetic retinopathy. The discrepancy may be related to increasing homogeneity of retinopathy and diminishing power to detect small differences, but it may also reflect the uncertain and inconsistent effects of HLA-DR3 or DR4 on the development and progression of diabetic retinopathy.

Protection provided by Haemophilus influenzae type b conjugate vaccines in Los Angeles County : a case-control study

The objective was to assess the degree of disease control and to evaluate the protective efficacy of licensed Haemophilus influenzae type b (Hib) conjugate vaccines (HbOC, PRP-OMP, PRP-D) used routinely in children 2 to 35 months of age. We conducted a case-control study in Los Angeles County between January 1, 1991, and December 31, 1992, and a cohort analysis of Hib cases between 1983 and 1992. For the case-control study 105 cases of invasive Hib disease were identified and 767 geographically and age-matched controls were selected by random digit telephone dialing. Sixteen HbOC vaccine failures occurred > 14 days after a single dose of vaccine, 6 vaccine failures after 2 doses and 3 failures after 3 doses; 2 cases occurred 6 and 12 days, respectively, after an initial dose of HbOC. The protective efficacy of a single HbOC vaccine dose was 71.1% (95% confidence interval (CI), 37.5 to 87.2%). After 2 doses the efficacy was 88.8% (95% CI, 59.5 to 96.9%) and after 3 doses it was 94.4% (95% CI, 68.0% to 99.0%). Similar 95% CIs were seen for 1 and 2 doses of PRP-OMP vaccine. Adjustment of efficacy estimates for potential confounding variables did not significantly alter the results. Despite relatively low rates of immunization (20 to 60%) the rates of Hib disease decreased strikingly between 1990 and 1992 (from 24.2 to 4.4/100,000 children < 5 years of age). The HbOC conjugate vaccine, used predominantly but incompletely during this period, provided substantial protection against invasive Hib disease in children immunized between 2 and 35 months of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of association between hepatitis B birth immunization and neonatal death: a population-based study from the vaccine safety datalink project.

Background: There have been no population-based studies of the potential association between neonatal death and newborn immunization with hepatitis B vaccine (HBV). Methods: As part of the Vaccine Safety Datalink Project, we defined a birth cohort at Southern and Northern California Kaiser Permanente Health Plans of more than 350,000 live births from 1993 to 1998 and ascertained all deaths occurring under 29 days of age. We compared the proportions of deaths among birth HBV-vaccinated and unvaccinated newborns and reviewed the causes and circumstances of their deaths. We performed detailed clinical reviews of all HBV-vaccinated neonates who died and a sample of unvaccinated neonates who died and who were matched to vaccinated deaths for days of life, sex, birth year and site of care. To avoid confounding, we categorized the causes of death as either “expected” or “unexpected” and performed a stratified analysis to compare mortality with immunization status. Results: There were 1363 neonatal deaths during the study period. Whereas 67% of the entire birth cohort received HBV at birth, only 72 (5%) of the neonates who died were HBV-vaccinated at birth (P < 0.01). We found no significant difference in the proportion of HBV-vaccinated (31%) and unvaccinated (35%) neonates dying of unexpected causes (P = 0.6). Further we could not identify a plausible causal or temporal relationship between HBV administration and death for the 22 vaccinated neonates who died unexpectedly. Conclusions: A relationship between HBV and neonatal death was not identified.