A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers.

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing.

Prevalence of obesity was related to HLA-DQ in 2-4-year-old children at genetic risk for type 1 diabetes.

OBJECTIVES: Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. METHODS: Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. RESULTS: The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression model suggested DQ2/2 was associated with higher obesity risk at age 4 (odds ratio, 2.41; 95% confidence interval, 1.21-4.80) after adjusting for the development of islet autoantibody and/or type 1 diabetes. CONCLUSIONS: The HLA-DQ2/2 genotype may predispose to obesity among 2-4-year-old children with genetic risk for type 1 diabetes.

Clinical severity and quality of life in children and adolescents with Rett syndrome.

OBJECTIVE: The clinical features and genetics of Rett syndrome (RTT) have been well studied, but examination of quality of life (QOL) is limited. This study describes the impact of clinical severity on QOL among female children and adolescents with classic RTT. METHODS: Cross-sectional and longitudinal analyses were conducted on data collected from an NIH-sponsored RTT natural history study. More than 200 participants from 5 to 18 years of age with classic RTT finished their 2-year follow-up at the time of analysis. Regression models after adjustment for their MECP2 mutation type and age at enrollment were used to examine the association between clinical status and QOL. RESULTS: Severe clinical impairment was highly associated with poor physical QOL, but worse motor function and earlier age at onset of RTT stereotypies were associated with better psychosocial QOL; conversely, better motor function was associated with poorer psychosocial QOL. CONCLUSIONS: Standard psychosocial QOL assessment for children and adolescents with RTT differs significantly with regard to their motor function severity. As clinical trials in RTT emerge, the Child Health Questionnaire 50 may represent one of the important outcome measures.

Country-specific birth weight and length in type 1 diabetes high-risk HLA genotypes in combination with prenatal characteristics.

OBJECTIVE: To examine the relationship between high-risk human leukocyte antigen (HLA) genotypes for type 1 diabetes and birth size in combination with prenatal ch aracteristics in different countries. STUDY DESIGN: Four high-risk HLA genotypes were enrolled in the Environmental determinants of Diabetes in the Young study newborn babies from the general population in Finland, Germany, Sweden and the United States. Stepwise regression analyses were used to adjust for country, parental physical characteristics and environmental factors during pregnancy. RESULT: Regression analyses did not reveal differences in birth size between the four type 1 diabetes high-risk HLA genotypes. Compared with DQ 4/8 in each country, (1) DQ 2/2 children were heavier in the United States (P=0.028) mostly explained however, by parental weight; (2) DQ 2/8 (P=0.023) and DQ 8/8 (P=0.046) children were longer in Sweden independent of parents height and as well as (3) in the United States for DQ 2/8 (P=0.023), but again dependent on parental height. CONCLUSION: Children born with type 1 diabetes high-risk HLA genotypes have comparable birth size. Longitudinal follow-up of these children should reveal whether birth size differences between countries contribute to the risk for islet autoimmunity and type 1 diabetes.

An automated communication system in a contact registry for persons with rare diseases: scalable tools for identifying and recruiting clinical research participants.

OBJECTIVES: Strategies for study recruitment are useful in clinical research network settings. We describe a registry of individuals who have self-identified with one of a multiplicity of rare diseases, and who express a willingness to be contacted regarding possible enrollment in clinical research studies. We evaluate this registry and supporting tools in terms of registry enrollment and impact on participation rates in advertised clinical research studies. METHODS: A web-based automated system generates periodic and customized communications to notify registrants of relevant studies in the NIH Rare Diseases Clinical Research Network (RDCRN). The majority of these communications are sent by email. We compare the characteristics of those enrolled in the registry to the characteristics of participants enrolled in sampled RDCRN studies in order to estimate the impact of the registry on study participation in the network. RESULTS: The registry currently contains over 4000 registrants, representing 40 rare diseases. Estimates of study participation range from 6-27% for all enrollees. Study participation rates for some disease areas are over 40% when considering only contact registry enrollees who live within 100 mi of a clinical research study site. CONCLUSIONS: Automated notifications can facilitate consistent, customized, and timely communication of relevant protocol information to potential research subjects. Our registry and supporting communication tools demonstrate a significant positive impact on study participation rates in our network. The use of the internet and automated notifications make the system scalable to support many protocols and registrants.

Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

AIM: Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. METHODS: A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. RESULTS: Reliability of the measures was extremely high (intraclass correlations for the six measures all = 0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range = 0.77 to 0.95. The scores of the five acute activity measures correlated extremely well with one another. CONCLUSIONS: Currently available tools for measuring disease extent and activity in ANCA-associated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments.

Autoantibodies and human leucocyte antigen class II in first-degree family members of Mexican-American type 1 diabetic patients.

As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first-degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD(65)), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA+, 14 ICA-) was tested for GAD(65) and was found positive. 4/14 ICA+ first-degree relatives were GAD(65) positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands. These results suggest that autoimmunity occurs in type 1 diabetes families of Mexican descent in similar frequencies to that of non-Hispanic, Caucasian families. The presence of autoantibodies appears to be regulated in part by HLA class II genes, even in the absence of overt diabetes.

Economic analysis of cancer treatment costs: another tool for oncology managers.

Oncology managers increasingly need more information about how much and why treatment costs vary across cancer patients. In response to this need, our Center is building an analytic capacity for investigating economic aspects of cancer treatment. Economic analysis is characterized by a simultaneous consideration of treatment costs and outcomes; it focuses on how treatment cost/outcome ratios vary across patient populations with similar diseases. In this paper, we present an overview of our work, with special emphasis on the measurement of outcomes and the inputs or costs of treatment, the variability of cost/outcome ratios, and the analysis of the factors that predict or explain this observed variation. We illustrate how the analysis is conducted, set out selected results relating to lung and breast cancer patients, and assess some of the advantages and disadvantages of the approach. Among other things, we conclude that economic analysis of cancer treatment costs is feasible and that it can provide useful data for managerial decision making.

Expression of GAD65 and islet cell antibody (ICA512) autoantibodies among cytoplasmic ICA+ relatives is associated with eligibility for the Diabetes Prevention Trial-Type 1.

More than 71,000 relatives of type 1 diabetic patients have been screened for cytoplasmic islet cell antibodies (ICAs), GAD65 autoantibodies (GAAs), and ICA512 autoantibodies (ICA512AAs). Among those 71,148 relatives, 2,448 were cytoplasmic ICA+, and the remainder were ICA-. Of the ICA+ group, 1,229 (50.2%) were positive for GAAs and/or ICA512AAs. Among ICA- relatives, 1,897 (2.76%) were positive for GAAs and/or ICA512AAs. Given the large number of relatives positive for cytoplasmic ICA and negative for "biochemically" determined autoantibodies, and the converse, we analyzed the proportion of ICA+ relatives found eligible to participate in the intervention phase of Diabetes Prevention Trial-Type 1 (DPT-1). To be eligible for the parenteral insulin DPT-1 trial, a relative had to have first-phase insulin secretion below the 1st percentile of cut-points (for parents) or below the 10th percentile (for siblings and offspring). To be eligible for the oral insulin trial, a relative had to have first-phase insulin secretion above cut-points (>1st percentile for parents, >10th percentile for siblings/offspring) and be positive for anti-insulin autoantibodies. For both trials, DQB1*0602 was an exclusion criteria, cytoplasmic ICA positivity had to be confirmed, and an oral glucose tolerance test had to result in nondiabetic levels. Of 572 relatives found to be eligible for trial entry, 442 (77.3%) were positive for GAAs and/or ICA512AAs, although overall only 50.2% of ICA+ relatives were positive for GAAs and/or ICA512AAs. The positive predictive value for trial eligibility for ICA+ relatives with GAAs or ICA512AAs who completed staging was 51.0%. In contrast, only 11.9% of ICA+ but GAA- and ICA512AA- relatives were found to be eligible by DPT criteria for trial entry. Positivity for biochemically determined autoantibodies among cytoplasmic antibody-positive relatives is associated with eligibility for the DPT-1 study.

Impact of clinical trials on the cost of cancer care.

BACKGROUND: Empirical evidence on the economic impact of cancer clinical trials is in short supply, but it is widely assumed that clinical trials add at least 10% to overall costs. OBJECTIVES: To estimate how much, if at all, trial enrollment increases the use of scarce resources in treating breast, lung, lymphoma, and ovarian cancer patients. RESEARCH DESIGN: A profile of the cumulative charges for all inpatient and outpatient hospital care received by a sample of patients over an observation period beginning at diagnosis and continuing for upwards of 44 months postdiagnosis. Patients are classified by whether they were enrolled on an IRB-sanctioned research protocol and, if so, by the type of protocol. Both univariate and multivariate statistical tests are conducted to appraise whether cumulative charges differ between patients who were enrolled on key types of protocols and those who were not. SUBJECTS: Approximately 1,900 breast, lung, lymphoma, and ovarian cancer patients treated at a single center. MEASURES: Clinical endpoints and demographic, disease, and therapy characteristics of patients that drive treatment costs. RESULTS: Controlling for demographic and disease characteristics, initial therapy, and key endpoints, the net effect of trial participation on cumulative charges for hospital inpatient and outpatient care is never significantly positive at conventional confidence limits. This result is found for each of the four patient groups and three types of protocols encompassed by this analysis. CONCLUSIONS: Support for clinical trials by health care payers does not necessarily risk adding significantly to the cost of cancer care.

Type I diabetes manifested solely by 2-h oral glucose tolerance test criteria.

The clinical presentation of type 1 diabetes usually involves symptoms such as polyuria and polydipsia. However, investigators in the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) have detected a group of subjects with type 1 diabetes who have a different phenotype. These subjects are asymptomatic, have normal (<6.1 mmol/l) (group A) or impaired (6.1- <7.0 mmol/l) (group B) fasting glucose, but have 2-h glucose values >11.1 mmol/l on their oral glucose tolerance tests (OGTT). Of the 585 OGTTs performed on islet cell antibody (ICA)-positive relatives with insulin autoantibodies (IAA) or low first-phase insulin response (FPIR), normal glucose tolerance (NGT) was found in 427 subjects; impaired glucose tolerance (IGT) was found in 87 subjects, and diabetes was found by 2-h OGTT criteria alone in 61 subjects. Despite marked differences in 2-h glucose values (NGT 5.8 +/- 1.1 mmol/l, IGT 8.9 +/- 0.9 mmol/l, and group A 13.5 +/- 2.5 mmol/l), there were no significant differences in fasting glucose values among NGT (4.8 +/- 0.5 mmol/l), IGT (5.03 +/- 0.5 mmol/l), and group A (4.99 +/- 0.7 mmol/l) categories. Mean FPIR was higher in subjects with NGT compared with subjects with IGT and subjects diagnosed by 2-h OGTT criteria alone. However, the correlation between FPIR and 2-h glucose value was low (r2 = 0.114). Multivariate analysis demonstrated that additional independent variables provide smaller contributions to the 2-h glucose value. In conclusion, there are asymptomatic type 1 diabetic subjects whose diabetes was diagnosed by the 2-h criteria on OGTT alone. Despite the importance of beta-cell dysfunction in the pathogenesis of type I diabetes, factors other than impaired FPIR must also contribute to postprandial glucose tolerance in these subjects.

First-phase insulin release during the intravenous glucose tolerance test as a risk factor for type 1 diabetes.

OBJECTIVE: To determine the relationship between first-phase (1 minute + 3 minutes) insulin production during the intravenous glucose tolerance test (IV-GTT) and risk factors for developing type 1 diabetes. STUDY DESIGN: Relatives of persons with type 1 diabetes (n = 59,600) were screened for islet cell antibodies (ICAs). Subjects who had positive screening results underwent IV-GTT (> or =2 times), repeat ICA screening, insulin autoantibody (IAA) screening twice, and an oral glucose tolerance test. RESULTS: Of the 59,600 subjects in the study, 2199 (3.69%) had positive findings on initial ICA test. IV-GTTs were performed in 1622 subjects, with children <8 years having the lowest first-phase insulin release (FPIR) and subjects 8 to 20 years of age having the highest FPIR. The FPIR was lower for subjects with a confirmed positive ICA test result or a positive IAA test result, subjects with higher titers of ICA or IAA, and subjects who had an abnormal (impaired or diabetic) oral glucose tolerance test result. CONCLUSION: FPIR in the IV-GTT correlates strongly with risk factors for development of type 1 diabetes.

Effects of health insurance and race on colorectal cancer treatments and outcomes.

OBJECTIVES: We hypothesized that health insurance payer and race might influence the care and outcomes of patients with colorectal cancer. METHODS: We examined treatments received for all incident cases of colorectal cancer occurring in Florida in 1994 (n = 9551), using state tumor registry data. We also estimated the adjusted risk of death (through 1997), using proportional hazards regression analysis controlling for other predictors of mortality. RESULTS: Treatments received by patients varied considerably according to their insurance payer. Among non-Medicare patients, those in the following groups had higher adjusted risks of death relative to commercial fee-for-service insurance: commercial HMO (risk ratio [RR] = 1.40; 95% confidence interval [CI] = 1.18, 1.67; P = .0001), Medicaid (RR = 1.44; 95% CI = 1.06, 1.97; P = .02), and uninsured (RR = 1.41; 95% CI = 1.12, 1.77; P = .003). Non-Hispanic African Americans had higher mortality rates (RR = 1.18; 95% CI = 1.01, 1.37; P = .04) than non-Hispanic Whites. CONCLUSIONS: Patients with colorectal cancer who were uninsured or insured by Medicaid or commercial HMOs had higher mortality rates than patients with commercial fee-for-service insurance. Mortality was also higher among non-Hispanic African American patients.

Increasing supplies of dermatologists and family physicians are associated with earlier stage of melanoma detection.

BACKGROUND: Physicians are important in the early detection of melanoma. We investigated whether primary care physician supply and the supply of dermatologists were related to stage at diagnosis for malignant melanoma. METHODS: From the state tumor registry in Florida in 1994, we identified incident cases of malignant melanoma for which stage at diagnosis was available (N = 1884). Data on physician supply was obtained from the 1994 American Medical Association Physician Masterfile. Logistic regression determined the effects of physician supply (at the ZIP code level) on the odds of early-stage diagnosis controlling for patients' age, gender, race/ethnicity, marital status, education level, income level, comorbidity, and type of health insurance. RESULTS: Each additional dermatologist per 10,000 population was associated with a 39% increased odds of early diagnosis (odds ratio = 1.39, 95% confidence interval [CI] 1.09-1.70, P =.010). For each additional family physician per 10,000 population, the odds of early diagnosis increased 21% (odds ratio = 1.21, 95% CI 1.09-1.33, P <.001). Each additional general internist per 10,000 population was associated with a 10% decrease in the odds of early-stage diagnosis (odds ratio = 0.90, 95% CI 0.83-0.98, P =.009). The supplies of general practitioners, obstetrician/gynecologists, and other nonprimary care specialists were not associated with stage at diagnosis. CONCLUSIONS: Increasing supplies of dermatologists and family physicians were associated with earlier detection of melanoma. In contrast, increasing supplies of general internists were associated with reduced odds of early detection. Our findings suggest that the composition of the physician work force may affect important health outcomes and needs further study.

Oral methotrexate for recurrent brain tumors in children: a Pediatric Oncology Group study.

PURPOSE: Children with recurrent or progressive central nervous system (CNS) tumors have an unfavorable prognosis. Based on Pediatric Oncology Group (POG) institutional pilot data, low-dose oral methotrexate (MTX) was studied. METHODS: Eight dosages of MTX 7.5 mg/m2 every 6 hours were administered on a weekly schedule for as long as 18 months. Patients in six different brain tumor strata were accrued. RESULTS: The response rates (complete or partial responses) were as follows: astrocytoma 2 of 10, malignant glioma 1 of 19, medulloblastoma 0 of 18, brainstem tumor 0 of 12, ependymoma 1 of 7, and miscellaneous histologic types 0 of 12. The main toxicities, mucositis, myelosuppression, and hepatic transaminase elevation were considered tolerable. CONCLUSION: Low-dose oral MTX showed no significant activity against malignant glioma, medulloblastoma, brainstem tumors, and miscellaneous histologic types. Indeterminate but low response rates were observed in children with astrocytoma and ependymoma. This regimen will not be recommended for front-line therapy.

Islet cell antibody-positive relatives with human leukocyte antigen DQA1*0102, DQB1*0602: identification by the Diabetes Prevention Trial-type 1.

The presence of human leukocyte antigen (HLA) haplotype DQA1*0102, DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type 1 has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African-American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes [insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)] than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Although half of the ICA+ DQB1*0602 relatives had a high risk second haplotype, this was not associated with the additional risk factors for diabetes. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. In conclusion, the presence of ICA in the relatives described here suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, there may be different effects of DQB1*0602 between ethnic groups.

Effects of health insurance and race on breast carcinoma treatments and outcomes.

BACKGROUND: The authors hypothesized that insurance payer and race would influence the care and outcomes for patients with breast carcinoma. METHODS: The authors examined treatments and adjusted risk of death (through 1997) for all incident cases of breast carcinoma occurring in Florida in 1994 (n = 11,113) by using state tumor registry data. RESULTS: Patients lacking health insurance were less likely to receive breast-conserving surgery (BCS) compared with patients who had private health insurance. Among patients insured by Medicare, those belonging to a health maintenance organization (HMO) were more likely to receive BCS but less likely to receive radiation therapy after BCS. Non-Hispanic African Americans had higher mortality rates even when stage at diagnosis, insurance payer, and treatment modalities used were adjusted in multivariate models (adjusted risk ratio [RR], 1.35; 95% confidence interval [CI], 1.12-1.61; P = 0.001). Patients who had HMO insurance had similar survival rates compared with those with fee-for-service (FFS) insurance. Among non-Medicare patients, mortality rates were higher for patients who had Medicaid insurance (RR, 1.58, 95% CI, 1.18-2.11; P = 0.002) and those who lacked health insurance (RR, 1.31; 95% CI, 1.03-1.68; P = 0.03) compared with patients who had commercial FFS insurance. There were no insurance-related differences in survival rates, however, once stage at diagnosis was controlled. CONCLUSIONS: As a result of later stage at diagnosis, patients with breast carcinoma who were uninsured, or insured by Medicaid, had higher mortality rates. Mortality rates were also higher among non-Hispanic African Americans, a finding that was not fully explained by differences in stage at diagnosis, treatment modalities used, or insurance payer.

Effects of health insurance and race on early detection of cancer.

BACKGROUND: The presence and type of health insurance may be an important determinant of cancer stage at diagnosis. To determine whether previously observed racial differences in stage of cancer at diagnosis may be explained partly by differences in insurance coverage, we studied all patients with incident cases of melanoma or colorectal, breast, or prostate cancer in Florida in 1994 for whom the stage at diagnosis and insurance status were known. METHODS: The effects of insurance and race on the odds of a late stage (regional or distant) diagnosis were examined by adjusting for an individual's age, sex, marital status, education, income, and comorbidity. All P values are two-sided. RESULTS: Data from 28 237 patients were analyzed. Persons who were uninsured were more likely diagnosed at a late stage (colorectal cancer odds ratio [OR] = 1.67, P =.004; melanoma OR = 2.59, P =.004; breast cancer OR = 1.43, P =.001; prostate cancer OR = 1.47, P =.02) than were persons with commercial indemnity insurance. Patients insured by Medicaid were more likely diagnosed at a late stage of breast cancer (OR = 1.87, P<.001) and melanoma (OR = 4.69, P<.001). Non-Hispanic African-American patients were more likely diagnosed with late stage breast and prostate cancers than were non-Hispanic whites. Hispanic patients were more likely to be diagnosed with late stage breast cancer but less likely to be diagnosed with late stage prostate cancer. CONCLUSIONS: Persons lacking health insurance and persons insured by Medicaid are more likely diagnosed with late stage cancer at diverse sites, and efforts to improve access to cancer-screening services are warranted for these groups. Racial differences in stage at diagnosis are not explained by insurance coverage or socioeconomic status.