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Biomedical subjects

M Knip

Publications and source records attributed to M Knip.

At least 145 records · Page 8Linked to original sources
PubMed1997

Islet cell antibody seroconversion in children is temporally associated with enterovirus infections. Childhood Diabetes in Finland (DiMe) Study Group.

Exposure to Coxsackie B virus or other enteroviruses prenatally or in childhood increases the risk for later manifestation of insulin-dependent diabetes mellitus (IDDM). The occurrence of enterovirus infections was analyzed in 23 initially nondiabetic and islet cell antibody (ICA)-negative siblings of IDDM patients who converted to ICA positivity during a prospective follow-up study. Increases in enterovirus antibody levels, documented by heavy chain-capture RIA and EIA techniques, were significantly more frequent in sample intervals in which ICA first appeared (18/23, 78%) than in other sample intervals in these siblings (30/92, 33%; P < .001) or all sample intervals in 97 ICA-negative control siblings (117/403, 29%; P < .001). The children who converted to ICA positivity during an enterovirus infection more often had the high-risk HLA-DQB1 genotype than did children who were constantly ICA-negative (P < .01). The results suggest that enteroviruses may be important in the induction of a beta cell damaging process long before the clinical manifestation of IDDM.

Adolescent↗
PubMed1997

HLA-DQB1*0304-DRB1*0408 haplotype associated with insulin-dependent diabetes mellitus in populations in the eastern Baltic region.

The rare HLA-DQB1*0304 allele was found increased among IDDM patients in the populations of the eastern Baltic region. Its frequency among IDDM patients was 4.5% (20/443) compared to 1.1% (9/853) in healthy controls in the combined series of Estonian, Latvian and St. Petersburg Russian populations (P=0.0001). HLA-DQB1*0304 in these populations was associated with DRB1*0408, and the haplotype was further characterized by a B35 allele and a typical combination of microsatellite markers from the TNF gene region. The result is compatible with the significance of the 57th amino acid in the DQ beta-chain but also emphasizes the importance of alleles in other HLA loci adjacent to DQ in the determination of IDDM susceptibility.

Baltic States↗
PubMed1997

Reduced levels of growth hormone, insulin-like growth factor-I and binding protein-3 in patients with shunted hydrocephalus.

OBJECTIVE: Children with hydrocephalus are characterised by slow linear growth in prepuberty, accelerated physical maturation during puberty, and reduced final height. We aimed to study the possible roles of growth hormone, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) in this growth pattern. STUDY DESIGN: One hundred and fourteen patients with shunted hydrocephalus (62 males) aged 5 to 20 years, of whom 17 had spina bifida (six males), and 73 healthy controls (38 males) were studied. Anthropometric measures, body mass index, and body fat mass were assessed and the stage of puberty was determined. Serum growth hormone and plasma IGF-I and IGFBP-3 concentrations were measured. RESULTS: The patients comprised 44 (26 males) who were prepubertal and 70 (36 males) pubertal or postpubertal, while 32 of the controls (19 males) were prepubertal and 41 (19 males) pubertal or postpubertal. The prepubertal children with hydrocephalus had lower IGF-I (p = 0.002) and IGFBP-3 concentrations (p < 0.001) than the controls, and the pubertal children had four times lower basal growth hormone concentrations (p < 0.001). There was a correlation between height SD score and IGF-I levels in the total patient population (r = 0.23; p = 0.01). Peripheral IGF-I concentrations peaked at pubertal stages 2-3 in the female patients and at stage 4 in the controls. The prepubertal patients on antiepileptic treatment, carbamazepine in most cases (73%), had higher IGF-I (p = 0.01) and IGFBP-3 concentrations (p = 0.03) than those who had never been treated with antiepileptic drugs, but still lower IGFBP-3 levels than the controls (p = 0.01). CONCLUSION: Based on these findings, it can be concluded that reduced growth hormone secretion may contribute to the pattern of slow linear growth and reduced final height observed in these patients.

Adolescent↗
PubMed1997

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland.

OBJECTIVE: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years. DESIGN AND METHODS: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years. RESULTS: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative. CONCLUSION: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.

Adolescent↗
PubMed1997

Collagen metabolites in the prediction of response to GH therapy in short children.

To evaluate the role of collagen metabolites in the prediction of the response to GH treatment we measured the serum concentrations of the C-terminal propeptide of type I procollagen (PICP) and the N-terminal propeptide of type III procollagen (PIIINP) with specific RIAs in 35 short children (16 boys) before and after 5 days, 5 weeks and 3 months of GH therapy. The mean age of the children was 10.3 years (range 1.9-16.4 years) and the bone age ranged from 1.2 to 12.5 years (mean 7.6 years). The initial mean relative height (RH) was -3.6 SDS (range -6.6 to -2.4 S.D.). Nineteen children were found to have GH deficiency (GHD; peak GH responses in two pharmacological tests < 10 micrograms/l), while the remaining 16 were considered to have undefined short stature (USS). The children were treated with recombinant human GH (0.1 U/kg given subcutaneously at bedtime 6-7 times/week). The increases in RHI over the first 6 and 12 months of therapy were used as response measures. There was already a significant increase (P < 0.001) in both the serum PICP and PIIINP levels at 5 days, and the concentrations continued to rise up to 3 months, PICP levels rising less than the PIIINP levels. In the whole group the RHI over 6 months correlated most strongly with the absolute PICP concentrations at 3 months (rS = 0.59; P < 0.05), while the absolute PIIINP concentrations at 3 months showed the strongest relation to the one year RHI (rS = 0.69; P < 0.001). In the GHD group the 6 month RHI was most strongly related to the absolute PICP concentration at 3 months (rS = 0.59; P < 0.05). In the USS group the absolute PICP concentrations at 3 months correlated most strongly with the one year RHI (rS = 0.82; P < 0.01). Significant correlations were also observed between the absolute PIIINP levels at 3 months and the 6 month RHI (rS = 0.60; P < 0.05) and 12 month RHI (rS = 0.76; P < 0.01) in this group. These results show that GH therapy results in an unequivocal increase in circulating concentrations of PICP and PIIINP. The serum PICP and PIIINP concentrations may be of value in the prediction of the long-term response to GH therapy.

Adolescent↗
PubMed1997

Severe antibody-mediated human insulin resistance: successful treatment with the insulin analog lispro. A case report.

OBJECTIVE: To evaluate the efficacy of the insulin analog lispro (Lys B28, Pro B29) in severe insulin resistance caused by human insulin antibodies. CASE: A 27-year-old man with a history of diabetes treated with human insulin for 3 years developed severe immunological insulin resistance caused by human insulin antibodies. Throughout follow-up (12 months) the insulin analog lispro was administered with an infusion pump as the only insulin therapy. The insulin dose decreased from an average of 300 U/day to 58 U/day, HbA1c decreased from 12.6 to 7.4%, and human insulin antibodies decreased from 8,057 to 1,860 nU/ml. Hypoglycemic episodes during early morning disappeared. CONCLUSIONS: The insulin analog lispro might be suitable for the treatment of diabetic patients with substantially increased insulin antibody levels Apparently, the structural difference between the lispro and human insulin molecules prevented lispro from binding to the human insulin antibodies in this patient and consequently was nonimmunogenic.

Adult↗
PubMed1997

Childhood cancer and later development of the metabolic syndrome.

The improving survival rate of patients with childhood cancer has led to a growing awareness of the long-term effects of malignant disease and its treatment. Various endocrine abnormalities have been reported as frequent long-term adverse effects of cancer treatment in childhood, and among these growth hormone (GH) deficiency is the most common one, especially after cranial irradiation. Besides promoting growth, GH has well-established metabolic effects. Patients with GH deficiency tend to be obese, and obesity per se is also associated with insulin resistance which plays a key role in a cluster of metabolic derangements including glucose intolerance, hypertension, lipid abnormalities and atherosclerotic cardiovascular disease. This condition is known as the metabolic syndrome. Our recent observations indicate that a combination of obesity, glucose intolerance, hyperinsulinaemia and an abnormal lipid profile can be observed in long-term survivors of childhood cancer. Every sixth patient had the triad of obesity, hyperinsulinaemia and low HDL cholesterol, whereas this combination was not seen in any of the controls. The survivors with such a high-risk profile for cardiovascular disease had markedly reduced spontaneous GH secretion, and also additional features of the metabolic syndrome, such as higher systolic blood pressure and higher plasma glucose and serum triglyceride levels. Accordingly, decreased GH secretion, or alternatively some other disturbance in the hypothalamic-pituitary axis, emerging as a consequence of cranial radiation, may expose long-term survivors of childhood cancer to premature evolution of the metabolic syndrome. This can have an important impact on the long-term prognosis in these patients, because the syndrome as such results in an increased risk of cardiovascular morbidity and mortality.

Adolescent↗
PubMed1997

From pathomechanisms to prediction, prevention and improved care of insulin-dependent diabetes mellitus in children.

Molecular biology, gene technology and immunology have extensively clarified the aetiology and pathogenesis of insulin-dependent diabetes mellitus (IDDM). It is now obvious that the genetic background of the individual, poorly characterized environmental factors and aggressive autoimmune phenomena in a complex interplay contribute to the progression to clinical IDDM. The IDDM risk associated with certain genetic markers, e.g. the risk alleles at various HLA loci, the most strongly predisposing gene region, and the mechanisms that mediate the genetic impact may differ in different populations. In Finland the accumulated genetic evidence is so convincing that two IDDM prevention studies have been initiated. One is a population-based prediction and prevention study, while the other is conducted in first-degree relatives of IDDM patients. Both studies rely on screening of newborn infants for IDDM susceptibility alleles at the HLA-DQB1 locus. Meanwhile, in the clinical care of children with IDDM, the importance of intensified and individualized insulin therapy in prevention of diabetic microangiopathy has become increasingly clear, and should be implemented in the care of most paediatric patients.

Child↗
PubMed1997

Disease-associated autoimmunity and prevention of insulin-dependent diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease with a subclinical prodromal period characterized by selective destruction of insulin-producing beta cells in the pancreatic islets. This process is assumed to be T-cell mediated, but the emergence of disease-associated autoantibodies into the peripheral circulation is usually the first noticeable sign of beta-cell autoimmunity in human IDDM. Recent observations have suggested that beta-cell autoimmunity may be induced in any individual at any time. There are also data indicating that such autoimmunity may have been initiated prenatally in some individuals. Only a proportion of those with signs of islet cell autoimmunity progress to clinical disease, and harmless beta-cell autoimmunity reflected by positivity for a single autoantibody specificity seems to appear without any relation to genetic IDDM susceptibility. One can hypothesize that in most subjects HLA-conferred protection against IDDM prevents the beta-cell process from progressing to a stage of destructive insulitis that may lead to clinical disease. Environmental factors may trigger initial beta-cell damage and subsequently accelerate the destructive process. Non-HLA genes may also be involved in the regulation of the progression rate. Prospective observations of prediabetic individuals have revealed that IDDM-associated autoantibodies tend to appear sequentially, and that those who progress to clinical disease mount a strong humoral immune response to most known disease-associated antigens. This indicates that the immune response associated with beta-cell destruction is not purely T-helper 1 biased. Antigen-specific immunotherapy may in the future offer effective measures to intervene in preclinical IDDM to prevent end-stage insulitis. Substantially more data have to be generated, however, on the mechanisms, efficacy and safety of such therapy before it is possible to judge its clinical applicability.

Autoimmunity↗
PubMed1996

HLA-DQB1-defined genetic susceptibility, beta cell autoimmunity, and metabolic characteristics in familial and nonfamilial insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group.

Familial aggregation of insulin-dependent diabetes mellitus (IDDM) is a common phenomenon, but the reasons behind it are poorly understood. To investigate whether there is heterogeneity between familial and nonfamilial forms of IDDM we compared genetic, immunological, and clinical characteristics of diabetic children with and without an affected first-degree relative in a population-based series of Finnish children with IDDM. The frequencies of HLA-DQB1 genotypes known to be associated with high (DQB1*0302/0201) or moderate (*0302/x) IDDM risk in the Finnish population were increased, while the proportions of DQB1 genotypes associated with low or decreased risk for IDDM were reduced in the 121 familial cases as compared with the 574 nonfamilial cases (32.7 vs. 21.3%, 41.3 vs. 35.9%, 18.3 vs. 31.4%, and 7.7 vs. 11.4%, respectively; P = 0.002). The frequencies and serum concentrations of islet cell antibodies, insulin autoantibodies, and antibodies to the 65-kD isoform of glutamic acid decarboxylase were similar at diagnosis in the familial and nonfamilial cases. The 31 first-affected cases in the multiple case families were younger at diagnosis than the nonfamilial cases (6.9 vs. 8.5 yr; P < 0.05). The 90 second-affected familial cases had less severe metabolic decompensation at diagnosis than either the first-affected familial or nonfamilial cases. In conclusion, familial aggregation of IDDM in Finland is at least partly explained by a higher frequency of IDDM susceptibility genes in families with multiple affected individuals. The lack of differences in autoantibody levels between the familial and nonfamilial cases indicates homogeneity rather than heterogeneity in the pathogenetic process of beta cell destruction.

Adolescent↗
PubMed1996

Identification and characterization of glima 38, a glycosylated islet cell membrane antigen, which together with GAD65 and IA2 marks the early phases of autoimmune response in type 1 diabetes.

Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD65, and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic beta cell destruction and development of type 1 diabetes. Here we identify a third islet cell autoantigen, a novel 38-kD protein, which is specifically immunoprecipitated with sera from a subset of prediabetic individuals and newly diagnosed type 1 diabetic patients. The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD65 and IA2. Removal of N-linked carbohydrates results in a protein of 22,000 Mr. Glima 38 autoantibodies were detected in 16/86 (19%) of newly diagnosed patients, including three very young children, who had a rapid onset of disease, and in 6/44 (14%) of prediabetic individuals up to several years before clinical onset. The cumulative incidence of GAD65 and glima 38 antibodies in these two groups was 83 and 80%, respectively, and the cumulative incidence of GAD65, glima 38, and IA2 antibodies in the same groups was 91 and 84%, respectively. GAD65, IA2, and glima 38 represent three distinct targets of immunoprecipitating IgG autoantibodies associated with beta cell destruction and type 1 diabetes.

Adolescent↗
PubMed1996

Clinical characteristics and factors affecting growth in long-term survivors of cancer.

We evaluated clinical characteristics and growth in 51 (24 males) long-term survivors of childhood cancer (median follow up 12.7 years). Patients were shorter, had a higher proportion of body fat and higher systolic blood pressure than their controls. The change in relative height during treatment was -0.83 standard deviation score (S.D.S.) in patients with cranial irradiation and -0.32 S.D.S. in patients without cranial irradiation; the figures after treatment were -0.56 and 0.20 S.D.S., respectively. Half (r2 = 0.50) of the variation in growth retardation during therapy could be explained by the cumulative doses of 6-mercaptopurine (6-MP) and vincristine and relative height at diagnosis. Cranial irradiation, increased relative height at diagnosis and young age at diagnosis were significant predictors of growth failure over the total observation period, explaining 43% of the variation. We conclude that long-term survivors of childhood cancer have impaired linear growth, increased body fat mass and elevated systolic blood pressure. Young children who are tall for their age at diagnosis and treated with cranial irradiation have the highest risk of impaired growth after the diagnosis. High doses of 6-MP seem to contribute significantly to growth retardation during therapy.

Adolescent↗
PubMed1996

Obesity and endocrine disorders in women taking valproate for epilepsy.

We recently reported the frequent occurrence of polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy, especially when the medication was started before the age of 20 years. In the present study we evaluated the association of obesity and hyperinsulinemia with valproate-related polycystic ovaries and hyperandrogenism in women with epilepsy. Sixty-five women participated in the study. Twenty-two received valproate monotherapy and 43 received carbamazepine monotherapy. In addition to clinical examination, vaginal ultrasonography was performed to determine ovarian size, and the concentrations of serum sex hormones, insulin, insulin-like growth factor 1, and the insulin-like growth factor-binding proteins 1 and 3 (IGFBP-1 and IGFBP-3) were measured. Fifty-nine percent of the women on valproate were obese, and in a retrospective analysis an indisputable weight gain (mean, 21 kg; range, 8-49 kg) was found in 50% of the women taking valproate. Fourteen (64%) of the women on valproate had polycystic ovaries, hyperandrogenism, or both. These women were obese, and in addition to elevated serum androgen levels, they had high concentrations of fasting serum insulin and low levels of serum insulin-like growth factor-binding protein 1. Valproate therapy for epilepsy is associated with weight gain during treatment in approximately 50% of women patients. The weight gain can be progressive, and is associated with hyperinsulinemia and low serum levels of insulin-like growth factor-binding protein 1, which may lead to hyperandrogenism and polycystic ovaries.

Adult↗
PubMed1996

Adrenal steroidogenesis is related to insulin in hyperandrogenic women.

OBJECTIVE: To evaluate ovarian and adrenal steroid secretion in women with severe hyperandrogenism. DESIGN: A prospective study. SETTING: The Gynecological Endocrine Research Unit of the University Central Hospital, Oulu, Finland. PATIENTS: Thirteen obese, hirsute women with severe hyperandrogenism. INTERVENTIONS: Adrenocorticotropin hormone stimulation and dexamethasone suppression tests and selective catheterizations of the left ovarian and adrenal veins were performed. MAIN OUTCOME MEASURES: The concentrations of insulin, P, 17-hydroxyprogesterone (17-OHP), androstenedione (A), T, DHEA, DHEAS, and cortisol were measured. RESULTS: The secretory gradients of T and its precursors, P, 17-OHP, A, and DHEA in the selective catheterizations showed the adrenal to be the main source of excessive steroid production in these patients. The concentrations of P (r = 0.82), 17-OHP (r = 0.89), A (r = 0.84), T (r = 0.86), and cortisol (r = 0.87) in the adrenal vein showed a strong correlation with insulin measured from the same samples. CONCLUSIONS: Excessive androgens were secreted mainly by the adrenals in these obese hyperinsulinemic women. Correlation analyses suggested that insulin stimulates adrenal androgen and cortisol secretion, which may constitute an important component of the pathogenetic mechanisms of hyperandrogenism and the polycystic ovary syndrome.

Adolescent↗
PubMed1996

Antibody cross-reactivity induced by the homologous regions in glutamic acid decarboxylase (GAD65) and 2C protein of coxsackievirus B4. Childhood Diabetes in Finland Study Group.

GAD65 contains an amino acid sequence which is highly homologous with a sequence in the 2C protein of coxsackievirus B4 (CBV4-2C). In the present study the possibility that this region could contain an epitope capable of inducing immunological cross-reactivity between CBV4-2C and GAD65 was evaluated. Six out of seven rabbit sera, which were raised against seven different synthetic peptides carrying various modifications of the homology sequence, showed cross-reactivity between 2C. GAD65 and GADD67 derived peptides in ELISA. There was substantial cross-reactivity between 2C and GAD65 peptides, but not between 2C and GAD67 peptides. The most cross-reactive peptides were those corresponding to the 2C sequences FIEWLKVKILPEVKEK and KILPEVKEKHEFLSRL. When the binding of the four 2C peptide-specific sera to the GAD65 protein was analysed in immunoprecipitation, two sera were found to be cross-reactive (anti-FIEWLKVKILPEVKEK and anti-WLKVKILPEVKEKHEF). One of these (anti-WLKVKILPEVKEKHEF) reacted also with coxsackie B virus (CBV)-infected cells. Antibodies against this epitope were induced during enterovirus (including CBV) infections in initially healthy children who later progressed to clinical insulin-dependent diabetes mellitus (IDDM). Antibody responses were frequent also in constantly GAD65 antibody-negative non-diabetic children, and antibody levels did not differ between newly diagnosed IDDM patients and matched control subjects. Blocking experiments confirmed that the observed reactivity of both rabbit and human antibodies was immunologically specific. The results suggest that the epitope is antigenically highly similar in 2C and GAD65, and that peptide immunization induces antibodies which cross-react with these molecules. However, the significance of this phenomenon in the pathogenesis of IDDM remains to be confirmed, as the peptide antibody levels were similar in patients with recent-onset IDDM and in control subjects.

Amino Acid Sequence↗
PubMed1996

Effect of polymorphism in the insulin gene region on IDDM susceptibility and insulin secretion. The Childhood Diabetes in Finland (DiMe) Study Group.

In addition to the major genetic determinants of insulin-dependent diabetes mellitus (IDDM) in the major histocompatibility complex (MHC) on chromosome 6, there are also minor genetic risk markers, e.g. in the insulin gene region on chromosome 11p15.5 (IDDM2). We studied the significance of the-23 HphI polymorphism in the insulin gene region (-23 HphI INS) in the Finnish population in combination with HLA genotyping data. The frequency of the-23 HphI INS +/+ genotype was higher in diabetic subjects with a low risk HLA DQB1 genotype than in control subjects (P = 0.05). Diabetic children in multiple-case families also had a higher frequency of the INS risk genotype than the controls (P < 0.05), and this difference was independent of the HLA genotype. Furthermore, we studied siblings positive for islet cell antibodies (ICAs) and/or insulin autoantibodies (IAAs) to evaluate the impact of the-23 HphI INS +/+ genotype on their beta-cell function assessed by sequential intravenous glucose tolerance tests and on their progression to IDDM. When analysing siblings with a low-risk HLA DQB1 genotype, those with the-23 HphI INS +/+ genotype had lower first phase insulin responses (P < 0.02) on several occasions than the remaining sibling. Six siblings (26.1%) in the former group progressed to clinical disease during the observation period, whereas none in the latter group presented with IDDM (P = 0.01). These observations suggest that the-23 HphI INS +/+ polymorphism is associated with an increased risk of IDDM in subjects without predisposing genes in the MHC region. The enhanced susceptibility may be related to a reduced insulin secretory capacity.

Adolescent↗
PubMed1996

Islet cell autoimmunity and progression to insulin-dependent diabetes mellitus in genetically high- and low-risk siblings of diabetic children. The Childhood Diabetes in Finland (DiMe) Study Group.

Insulin-dependent diabetes mellitus (IDDM) risk was evaluated in 765 siblings based on prospective observation of islet cell antibodies (ICAs) and insulin autoantibodies (IAAs) as a function of the degree of HLA identity to the proband and HLA-DR alleles. Twenty-eight (3.7%) siblings progressed to IDDM over a median observation period of 5.8 years. ICAs had higher sensitivity than IAAS (100% vs. 33% , P < 0.001), whereas persistent ICA positivity and double ICA/IAA positivity defined the highest actuarial risk (47% and 70%). Diabetes manifested after a mean of 3.2 years from the detection of ICAs in those siblings who were initially ICA negative and, importantly, the risk was equal to that of the siblings constantly positive from the first sample obtained. Although the combination of HLA identity and ICAs at or above 80 Juvenile Diabetes Foundation units carried the highest positive predictive value (77%), the high-risk HLA markers were insufficient to predispose siblings with low ICA levels to IDDM and low-risk HLA markers did not provide complete protection against high ICA levels and from subsequent IDDM. These results emphasize ICAs as the primary tool for risk evaluation in siblings followed by restricted HLA subtyping to reduce the population to be subjected to clinical intervention trials.

Actuarial Analysis↗