Pediatric Endocrinology Milestones 2.0-guide to their implementation.

The Milestones were initiated by the Accreditation Council for Graduate Medical Education (ACGME) to provide a framework for monitoring a trainee's progression throughout residency/fellowship. The Milestones describe stepwise skill progression through six core domains of clinical competency: Patient Care, Medical Knowledge, Interpersonal and Communication Skills, Practice-based Learning and Improvement, Professionalism, and Systems-based Practice. Since their introduction in 2013, several barriers to implementation have emerged. Thus, the ACGME launched the Milestones 2.0 project to develop updated specialty-specific milestones. The Pediatric Endocrinology Milestones 2.0 project aimed to improve upon Milestones 1.0 by addressing common limitations, providing resources for faculty to easily incorporate milestones into their assessment of trainees, and adding sub-competencies in health disparities, patient safety, and physician well-being.This paper reviews the development of the Pediatric Endocrinology Milestones 2.0 including the major changes from Milestones 1.0, development of the Supplemental Guide, and how Milestones 2.0 can be applied at the program level. Although use of the Milestones are required only for ACGME programs, the tools provided in Milestones 2.0 are applicable to fellowship programs worldwide.

Hepatic abnormalities in youth with Turner syndrome.

BACKGROUND & AIMS: Liver disease in children with Turner Syndrome (TS) is poorly understood relative to associated growth, cardiac and reproductive complications. This study sought to better characterize hepatic abnormalities in a large national cohort of youth with TS. METHODS: Using electronic health record data from PEDSnet institutions, 2145 females with TS were matched to 8580 females without TS on eight demographic variables. Outcomes included liver enzymes (AST and ALT) stratified as normal, 1-2 times above the upper limit of normal (ULN), 2-3 times ULN and >3 times ULN, as well as specific liver disease diagnoses. RESULTS: Fifty-eight percent of youth with TS had elevated liver enzymes. Patients with TS had higher odds of enzymes 1-2 times ULN (OR: 1.7, 95% CI: 1.4-1.9), 2-3 times ULN (OR: 2.7, 95% CI: 1.7-3.3) and >3 times ULN (OR: 1.7, 95% CI: 1.3-2.2). They also had higher odds of any liver diagnosis (OR: 2.4, 95% CI: 1.7-3.3), fatty liver disease (OR: 1.9, 95% CI: 1.1-3.2), hepatitis (OR: 3.7, 95% CI: 1.9-7.1), cirrhosis/fibrosis (OR: 5.8, 95% CI: 1.3-25.0) and liver tumour/malignancy (OR: 4.8, 95% CI: 1.4-17.0). In a multinomial model, age, BMI and presence of cardiovascular disease or diabetes significantly increased the odds of elevated liver enzymes in girls with TS. CONCLUSIONS: Youth with TS have higher odds for elevated liver enzymes and clinically significant liver disease compared with matched controls. These results emphasize the need for clinical screening and additional research into the aetiology and treatment of liver disease in TS. LAY SUMMARY: Turner Syndrome, a chromosomal condition in which females are missing the second sex chromosome, is often associated with short stature, infertility and cardiac complications. Liver abnormalities are less well described in the literature. In this study, nearly 60% of youth with TS have elevated liver enzymes. Furthermore, patients with TS had a diagnosis of liver disease more often than patients without TS. Our results support the importance of early and consistent liver function screening and of additional research to define mechanisms that disrupt liver function in paediatric TS females.

Congenital adrenal hyperplasia and the second newborn screen.

OBJECTIVE: To evaluate the effectiveness of a second newborn screen for congenital adrenal hyperplasia (CAH) in the state of Colorado and report characteristics associated with cases identified on the first versus second screen. STUDY DESIGN: Colorado implemented newborn screening for CAH with 17-hydroxyprogesterone beginning August 2000. The first screening is performed within 72 hours of life and the second between 8 and 14 days of life. We compared infants diagnosed on the basis of the first versus second newborn screen. RESULTS: The first screen identified 29 cases of which 28 represented classical CAH. The incidence of classical CAH on the first screen was 1:24,766. The second screen identified 17 additional cases, of which 11 represented classical CAH. Combined, the incidence of classical CAH was 1:17,789. The sensitivity of the first screen was 71.79%. The false negative rate of the first screen was 28.2%. In the absence of a second screen, 1:47,824 infants would have been missed. Infants diagnosed on the first screen had higher 17-hydroxyprogesterone values compared with those diagnosed on the second screen (P = .0008). CONCLUSIONS: The use of a single newborn screen for CAH missed nearly 30% of classical CAH cases in Colorado. Addition of a second screen, therefore, can improve the operating characteristics of the newborn screening program.

Androgens and estrogens synergistically regulate the expression of doublecortin and enhance neuronal recruitment in the song system of adult female canaries.

Vocal control nuclei in songbirds display seasonal changes in volume that are regulated by testosterone (T) and its androgenic (5α-dihydrotestosterone; DHT) or estrogenic (17ß-estradiol; E(2)) metabolites. In male canaries, T regulates expression of the microtubule-associated protein doublecortin (DCX), a marker of neurogenesis. We examined the effect of T and its two metabolites alone or in combination on DCX expression in adult female canaries. Treatment with T or with DHT+E(2) increased HVC volume and neuron numbers as well as the total numbers of fusiform (migrating) and round (differentiating) DCX neurons in the nucleus but generally not in adjacent areas. DHT or E(2) alone did not increase these measures but increased the density of fusiform DCX cells per section. Similar results were observed in area X, although some effects did not reach significance, presumably because plasticity in X is mediated transsynaptically and follows HVC changes with some delay. There was no effect of any treatment on the total number of neurons in area X, and no change in DCX cell densities was detected in the lateral magnocellular nucleus of the anterior nidopallium, nor in other parts of the nidopallium. DHT and E(2) by themselves thus increase density of DCX cells migrating through HVC but are not sufficient in isolation to induce the recruitment of these newborn neurons in the nucleus. These effects are generally not observed in the rest of the nidopallium, implying that steroids only act on the attraction and recruitment of new neurons in HVC without having any major effects on their production at the ventricle wall.

Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies.

CONTEXT: Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD). Progression to AD can take months to years, and early detection of metabolic decompensation may prevent morbidity and mortality. OBJECTIVE: To define optimal methods of predicting progression to overt AD (defined by subnormal peak cortisol response to Cosyntropin) in 21OH-AA+ individuals. DESIGN, SETTING AND PARTICIPANTS: Individuals were screened for 21OH-AA at the Barbara Davis Center from 1993 to 2011. Subjects positive for 21OH-AA (n = 87) were tested, and the majority prospectively followed for the development of Addison's disease, including seven diagnosed with AD upon 21OH-AA discovery (discovered), seven who progressed to AD (progressors) and 73 nonprogressors. MAIN OUTCOME MEASURED: Plasma renin activity (PRA), ACTH, baseline cortisol, peak cortisol and 21OH-AA were measured at various time points relative to diagnosis of AD or last AD-free follow-up. RESULTS: Compared with nonprogressors, in the time period 2 months-2 years prior to the onset of AD, progressors were significantly more likely to have elevated ACTH (11-22 pM, P < 1E-4), with no significant differences in mean PRA (P = 0·07) or baseline cortisol (P = 0·08), and significant but less distinct differences seen with 21OH-AA levels (P < 1E-4) and poststimulation cortisol levels (P = 6E-3). CONCLUSION: Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol, in the 2 months-2 years preceding the onset of AD.

Parental leave during pediatric fellowship training: A national survey.

BACKGROUND: Until recently, no uniform requirements for parental leave (PL) existed in graduate medical education. We implemented a national survey, with the objective of ascertaining fellows' perceptions of PL policies and their impact. This is the first study to focus exclusively on pediatric subspecialty fellows. METHODS: An online survey instrument was created targeting pediatric fellows. RESULTS: The survey was accessed by 1003 (25%) of the estimated 4078 pediatric subspecialty fellows and 853 (21%) submitted surveys. Respondent demographic data paralleled the data reported by the American Board of Pediatrics. Half of respondents did not know whether their program had a written PL policy. Over 40% reported ≥ 5 weeks of paid PL. Most indicated that fellows use vacation, sick leave, and unpaid time for PL. Almost half of respondents (45%) indicated that their program's PL policy increases the stress of having a child. Fellows chose establishing/extending paid leave and intentionally fostering a more supportive program culture as the most crucial candidate improvements. The importance of equitable PL polices between parent fellows and co-fellows was an important theme of our qualitative data. Fellows feel there is a moral misalignment between the field of pediatrics' dedication to maternal and child health and current PL policies governing pediatric trainees. CONCLUSIONS: PL policies vary widely among pediatric fellowship programs and are often not known by fellows. Fellows are not satisfied with PL policies, which often exacerbate stress for new parents and burden their co-fellows. Targeted modification of several aspects of PL policies may improve their acceptance.

From pattern to purpose: how comparative studies contribute to understanding the function of adult neurogenesis.

The study of adult neurogenesis has had an explosion of fruitful growth. Yet numerous uncertainties and challenges persist. Our review begins with a survey of species that show evidence of adult neurogenesis. We then discuss how neurogenesis varies across brain regions and point out that regional specializations can indicate functional adaptations. Lifespan and aging are key life-history traits. Whereas 'adult neurogenesis' is the common term in the literature, it does not reflect the reality of neurogenesis being primarily a 'juvenile' phenomenon. We discuss the sharp decline with age as a universal trait of neurogenesis with inevitable functional consequences. Finally, the main body of the review focuses on the function of neurogenesis in birds and mammals. Selected examples illustrate how our understanding of avian and mammalian neurogenesis can complement each other. It is clear that although the two phyla have some common features, the function of adult neurogenesis may not be similar between them and filling the gaps will help us understand neurogenesis as an evolutionarily conserved trait to meet particular ecological pressures.

Sex steroid-induced neuroplasticity and behavioral activation in birds.

The brain of adult homeothermic vertebrates exhibits a higher degree of morphological neuroplasticity than previously thought, and this plasticity is especially prominent in birds. In particular, incorporation of new neurons is widespread throughout the adult avian forebrain, and the volumes of specific nuclei vary seasonally in a prominent manner. We review here work on steroid-dependent plasticity in birds, based on two cases: the medial preoptic nucleus (POM) of Japanese quail in relation to male sexual behavior, and nucleus HVC in canaries, which regulates song behavior. In male quail, POM volume changes seasonally, and in castrated subjects testosterone almost doubles POM volume within 2 weeks. Significant volume increases are, however, already observable after 1 day. Steroid receptor coactivator-1 is part of the mechanism mediating these effects. Increases in POM volume reflect changes in cell size or spacing and dendritic branching, but are not associated with an increase in neuron number. In contrast, seasonal changes in HVC volume reflect incorporation of newborn neurons in addition to changes in cell size and spacing. These are induced by treatments with exogenous testosterone or its metabolites. Expression of doublecortin, a microtubule-associated protein, is increased by testosterone in the HVC but not in the adjacent nidopallium, suggesting that neuron production in the subventricular zone, the birthplace of newborn neurons, is not affected. Together, these data illustrate the high degree of plasticity that extends into adulthood and is characteristic of avian brain structures. Many questions still remain concerning the regulation and specific function of this plasticity.

Comparison of insulin autoantibody: polyethylene glycol and micro-IAA 1-day and 7-day assays.

BACKGROUND: Older studies of diabetes development typically utilized a 7-day incubation polyethylene glycol competitive insulin autoantibody assay (CIAA). Our standard micro-IAA assay (mIAA) utilizes precipitation with proteins A/G and 1-day incubation (1-day mIAA), but is less sensitive compared to the CIAA assay. METHODS: We performed CIAA and mIAA assays in various conditions. We analyzed serum samples from 446 type 1 diabetes patients, from another set of 247 type 1 diabetes patients within 2 weeks of initiation of insulin treatment, from 150 healthy control donors, from 22 healthy participants in the diabetes autoimmunity study in the young (DAISY), and also coded sera from 50 patients with newly diagnosed type 1 diabetes and 50 blood donor control samples. RESULTS: In the process of our study, we found that the key condition was the incubation time. Therefore, we extended the incubation time to 7 days (7-day mIAA assay). No CIAA-negative control was positive with either 1-day or 7-day mIAA. In a new onset type 1 diabetes and at risk cohorts (DAISY study), the 7-day mIAA identified an additional 18% as being positive along with 16% of those who were initially 1-day mIAA negative and CIAA positive. Most subjects detectable only with the 7-day mIAA assay had intermediate levels of CIAA (80-300 nU/mL) (p = 0.01). CONCLUSIONS: The 7-day mIAA assay identifies a small but significant additional subset of individuals positive on the CIAA assay, while preserving specificity.

Sex and regional differences in estradiol content in the prefrontal cortex, amygdala and hippocampus of adult male and female rats.

In general, the behavioral and neural effects of estradiol administration to males and females differ. While much attention has been paid to the potential structural, cellular and sub-cellular mechanisms that may underlie such differences, as of yet there has been no examination of whether the differences observed may be related to differential uptake or storage of estradiol within the brain itself. We administered estradiol benzoate to gonadectomized male and female rats, and compared the concentration of estradiol in serum and brain tissue found in these rats to those of gonadectomized, oil-treated rats and intact rats of both sexes. Long-term gonadectomy (3 weeks) reduced estradiol concentration in the male and female hippocampus, but not in the male or female amygdala or in the female prefrontal cortex. Furthermore, exogenous treatment with estradiol increased estradiol content to levels above intact animals in the amygdala, prefrontal cortex and the male hippocampus. Levels of estradiol were undetectable in the prefrontal cortex of intact males, but were detectable in all other brain regions of intact rats. Here we demonstrate (1) that serum concentrations of estradiol are not necessarily reflective of brain tissue concentrations, (2) that within the brain, there are regional differences in the effects of gonadectomy and estradiol administration, and (3) that there is less evidence for local production of estradiol in males than females, particularly in the prefrontal cortex and perhaps the hippocampus. Thus there are regional differences in estradiol concentration in the prefrontal cortex, amygdala and hippocampus that are influenced by sex and hormone status.

Celiac disease: pathophysiology, clinical manifestations, and associated autoimmune conditions.

The clinical spectrum of celiac disease continues to evolve. What was once thought to be a rare disorder affecting young children is now recognized to be very common with a range of symptoms from asymptomatic disease to severely affected persons. Screening for celiac disease has become relatively easily with reliable antibodies against self-antigens (TG) and modified environmental antigens (DGP). Diagnosis is confirmed by small intestinal biopsy with characteristic changes graded by the Marsh score. Elimination of gluten from the diet has been the standard of care for the last half century. Patients often have difficulty adhering to a gluten-free diet, and the failure of symptoms, antibody levels, or pathologic changes to improve after initiating the diet may be largely due to this difficulty. The genetic risk for celiac disease is largely related to HLA genotypes, with over 90% of subjects with celiac disease positive for DQ2 and the remainder positive for DQ8. The HLA association with celiac disease is largely accountable for its link to other autoimmune diseases, including type 1 diabetes and autoimmune thyroid disease, and the majority of risk for celiac disease in these populations is related to HLA genotype. Celiac disease also carries an increased risk for type 1 diabetes and autoimmune thyroid disease. Genetic syndromes such as Turner and Down syndromes are associated with an increased risk for celiac disease. Practitioners can identify groups of subjects at high risk for celiac disease and perform screening with celiac disease-related antibodies.

Pre-type 1 diabetes dysmetabolism: maximal sensitivity achieved with both oral and intravenous glucose tolerance testing.

OBJECTIVE: To determine the relationship of intravenous (IVGTT) and oral (OGTT) glucose tolerance tests abnormalities to diabetes development in a high-risk pre-diabetic cohort and to identify an optimal testing strategy for detecting preclinical diabetes. STUDY DESIGN: Diabetes Prevention Trial-Type 1 Diabetes (DPT-1) randomized subjects to oral (n = 372) and parenteral (n = 339) insulin prevention trials. Subjects were followed with IVGTTs and OGTTs. Factors associated with progression to diabetes were evaluated. RESULTS: Survival analysis revealed that higher quartiles of 2-hour glucose and lower quartiles of first phase insulin response (FPIR) at baseline were associated with decreased diabetes-free survival. Cox proportional hazards modeling showed that baseline body mass index (BMI), FPIR, and 2-hour glucose levels were significantly associated with an increased hazard for diabetes. On testing performed within 6 months of diabetes diagnosis, 3% (1/32) had normal FPIR and normal 2-hour glucose on OGTT. The sensitivities for impaired glucose tolerance (IGT) and low FPIR performed within 6 months of diabetes diagnosis were equivalent (76% vs 73%). CONCLUSIONS: Most (97%) subjects had abnormal IVGTTs and/or OGTTs before the development of diabetes. The highest sensitivity is achieved using both tests.

Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening.

CONTEXT: Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur together in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndrome I, autoimmune polyendocrine syndrome II, and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. EVIDENCE ACQUISITION: Review of the medical literature was performed with particular attention to the natural history, genetic factors, and syndromes associated with T1D, AIT, CD, and AD. EVIDENCE SYNTHESIS: Genetic risk for these diseases overlaps and includes genes within the major histocompatibility complex (MHC) such as the human leukocyte antigens (HLA) DR and DQ alleles and the MHC I-related gene A (MIC-A). Other genes outside of the MHC have been associated with these autoimmune diseases, including the gene encoding the lymphoid tyrosine phosphatase (PTPN22) and the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene. CONCLUSION: Genetic risk for T1D overlaps with AIT, CD, and AD. Disease risk is associated with organ-specific autoantibodies, which can be used to screen subjects with T1D.

Autoantibody "subspecificity" in type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct groups.

OBJECTIVE: Autoimmune thyroid disease (AIT), celiac disease, and Addison's disease are characterized by the presence of autoantibodies: thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in AIT, tissue transglutaminase antibody (TTGAb) in celiac disease, and 21-hydroxylase antibody (21-OHAb) in Addison's disease. The objective of this study was to define the prevalence of these autoantibodies and clinical disease in a population with type 1 diabetes. RESEARCH DESIGN AND METHODS: We screened 814 individuals with type 1 diabetes for TPOAb, TGAb, TTGAb, and 21-OHAb. Clinical disease was defined by chart review. Factors related to the presence of autoimmunity and clinical disease including age at onset of type 1 diabetes, duration of diabetes, age at screening, sex, and the presence of autoantibodies were reviewed. RESULTS: The most common autoantibodies expressed were TPOAb and/or TGAb (29%), followed by TTGAb (10.1%) and 21-OHAb (1.6%). Specific HLA DR/DQ genotypes were associated with the highest risk for expression of 21-OHAb (DRB1*0404-DQ8, DR3-DQ2) and TTGAb (DR3-DQ2- DR3-DQ2). The expression of thyroid autoantibodies was related to 21-OHAb but not to TTGAb. The presence of autoantibodies was associated with and predictive of disease. CONCLUSIONS: In this large cohort of individuals with type 1 diabetes, the expression of organ-specific autoantibodies was very high. The grouping of autoantibody expression suggests common factors contributing to the clustering.

Endocrine and immunogenetic testing in individuals with type 1 diabetes and 21-hydroxylase autoantibodies: Addison's disease in a high-risk population.

Individuals with type 1 diabetes mellitus (T1D) at risk for Addison's disease (AD) can be identified with RIAs for autoantibodies to the adrenal antigen 21-hydroxylase (21-OHAA). Screening individuals with T1D for 21OH-AA shows a relatively high prevalence of positive autoantibodies (1.4%, 38 of 2696 subjects). After detection of 21-OHAA, individuals were evaluated with endocrine testing, including baseline cortisol, ACTH, and plasma renin activity and low (1 mug) and high (250 mug) dose cortrosyn stimulation. Typing for DR and DQ alleles and for the major histocompatibility complex class I-related chain A (MICA) gene polymorphisms was performed. Six individuals were diagnosed with AD; five were identified on initial endocrine evaluation. Follow-up over 2.9 yr yielded one additional diagnosis of AD. Endocrine testing showed a correlation between baseline ACTH and peak cortisol (r = -0.61; P < 0.0001), baseline and peak cortisol (r = 0.70; P < 0.0001), and stimulated cortisol after low- and high-dose testing (r = 0.92; P < 0.0001). DR3-DQ2/DR4-DQ8 with DRB1* 0404 was associated with expression of 21-OHAA. At 2 yr, individuals homozygous for MICA5.1 had AD-free survival of 60% compared with 100% AD-free survival in those who were not homozygous for MICA5.1. Homozygosity for MICA5.1 may increase progression to overt AD among 21-OHAA-positive individuals.

Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up.

OBJECTIVE: The objective of this study was to determine whether earlier diagnosis of diabetes in prospectively followed autoantibody-positive children lowered onset morbidity and improved the clinical course after diagnosis. RESEARCH DESIGN AND METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows genetically at-risk children for the development of diabetes. Increased genetic risk is identified by family history of type 1 diabetes or expression of diabetes-associated HLA genotypes. Of the 2,140 prospectively followed children, 112 have developed islet autoantibodies and 30 have progressed to diabetes. Diabetes onset characteristics and early clinical course of these 30 children followed to diabetes were compared with those of 101 age- and sex-matched children concurrently diagnosed with diabetes in the community. RESULTS: Pre-diabetic children followed to diabetes were less often hospitalized than the community cases (3.3 vs. 44%; P < 0.0001). They had a lower mean HbA(1c) at onset (7.2 vs. 10.9%; P < 0.0001) and 1 month after diagnosis (6.9 vs. 8.6%; P < 0.0001) but not after 6 months of diabetes. The mean insulin dose was lower in the DAISY group at 1 (0.30 vs. 0.51 U. kg(-1). day(-1); P = 0.003), 6 (0.37 vs. 0.58; P = 0.001), and 12 months (0.57 vs. 0.72; P = 0.03). There was no difference in growth parameters between the two groups. Comparisons limited to children with a family history of type 1 diabetes in both groups showed a similar pattern. CONCLUSIONS: Childhood type 1 diabetes diagnosed through a screening and follow-up program has a less severe onset and a milder clinical course in the first year after diagnosis.

Hypo and Hyper: Common Pediatric Endocrine and Metabolic Emergencies.

The presentation of endocrine and metabolic emergencies represents one of the more challenging clinical scenarios faced by pediatricians and emergency providers. In this review, the authors attempt to describe some of the more common entities that a provider may see and provide a guide for the recognition and management of these difficult-to-assess and often very ill children.

Male song quality modulates c-Fos expression in the auditory forebrain of the female canary.

In canaries, specific phrases of male song (sexy songs, SS) that are difficult to produce are especially attractive for females. Females exposed to SS produce more copulation displays and deposit more testosterone into their eggs than females exposed to non-sexy songs (NS). Increased expression of the immediate early genes c-Fos or zenk (a.k.a. egr-1) has been observed in the auditory forebrain of female songbirds hearing attractive songs. C-Fos immunoreactive (Fos-ir) cell numbers were quantified here in the brain of female canaries that had been collected 30min after they had been exposed for 60min to the playback of SS or NS or control white noise. Fos-ir cell numbers increased in the caudomedial mesopallium (CMM) and caudomedial nidopallium (NCM) of SS birds as compared to controls. Song playback (pooled SS and NS) also tended to increase average Fos-ir cell numbers in the mediobasal hypothalamus (MBH) but this effect did not reach full statistical significance. At the individual level, Fos expression in CMM was correlated with its expression in NCM and in MBH but also with the frequency of calls that females produced in response to the playbacks. These data thus indicate that male songs of different qualities induce a differential metabolic activation of NCM and CMM. The correlation between activation of auditory regions and of the MBH might reflect the link between auditory stimulation and changes in behavior and reproductive physiology.

Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY).

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.