The epidemiology and natural history of pediatric primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC), and autoimmune hepatitis (AIH) are not well characterized. Using ...multiple, overlapping search strategies followed by a detailed records review, we identified all cases of pediatric PSC, ASC, AIH, and inflammatory bowel disease (IBD) in a geographically isolated region of the United States. We identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC, and 44 cases of AIH. The mean age at diagnosis was 13.0 years for PSC, 11.3 years for ASC, and 9.8 years for AIH. The incidence and prevalence of PSC, ASC, and AIH were 0.2 and 1.5 cases, 0.1 and 0.6 cases, and 0.4 and 3.0 cases per 100,000 children, respectively. The mean duration of follow‐up was 5.9 years. The probability of developing complicated liver disease within 5 years of the diagnosis of liver disease was 37% 95% confidence interval (CI) = 21%‐58% for PSC, 25% (95% CI = 7%‐70%) for ASC, and 15% (95% CI = 7%‐33%) for AIH. The 5‐year survival rates with the native liver were 78% (95% CI = 54%‐91%) for PSC, 90% (95% CI = 47%‐99%) for ASC, and 87% (95% CI = 71%‐95%) for AIH. Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%). PSC occurred in 9.9% of patients with ulcerative colitis (UC) and in 0.6% of patients with Crohn's disease (CD). ASC occurred in 2.3% of UC patients and 0.9% of CD patients. AIH occurred in 0.4% of UC patients and in 0.3% of CD patients. Liver disease occurred in 39 of 607 IBD patients (6.4%) overall. Conclusion: Immune‐mediated liver diseases are important sources of morbidity in children. Using a population‐based design, this study quantifies the burden and natural history of immune‐mediated liver disease in children. (Hepatology 2013;58:1392–1400)
Phevor integrates phenotype, gene function, and disease information with personal genomic data for improved power to identify disease-causing alleles. Phevor works by combining knowledge resident in ...multiple biomedical ontologies with the outputs of variant-prioritization tools. It does so by using an algorithm that propagates information across and between ontologies. This process enables Phevor to accurately reprioritize potentially damaging alleles identified by variant-prioritization tools in light of gene function, disease, and phenotype knowledge. Phevor is especially useful for single-exome and family-trio-based diagnostic analyses, the most commonly occurring clinical scenarios and ones for which existing personal genome diagnostic tools are most inaccurate and underpowered. Here, we present a series of benchmark analyses illustrating Phevor’s performance characteristics. Also presented are three recent Utah Genome Project case studies in which Phevor was used to identify disease-causing alleles. Collectively, these results show that Phevor improves diagnostic accuracy not only for individuals presenting with established disease phenotypes but also for those with previously undescribed and atypical disease presentations. Importantly, Phevor is not limited to known diseases or known disease-causing alleles. As we demonstrate, Phevor can also use latent information in ontologies to discover genes and disease-causing alleles not previously associated with disease.
The determination of the relationship between a pair of individuals is a fundamental application of genetics. Previously, we and others have demonstrated that identity-by-descent (IBD) information ...generated from high-density single-nucleotide polymorphism (SNP) data can greatly improve the power and accuracy of genetic relationship detection. Whole-genome sequencing (WGS) marks the final step in increasing genetic marker density by assaying all single-nucleotide variants (SNVs), and thus has the potential to further improve relationship detection by enabling more accurate detection of IBD segments and more precise resolution of IBD segment boundaries. However, WGS introduces new complexities that must be addressed in order to achieve these improvements in relationship detection. To evaluate these complexities, we estimated genetic relationships from WGS data for 1490 known pairwise relationships among 258 individuals in 30 families along with 46 population samples as controls. We identified several genomic regions with excess pairwise IBD in both the pedigree and control datasets using three established IBD methods: GERMLINE, fastIBD, and ISCA. These spurious IBD segments produced a 10-fold increase in the rate of detected false-positive relationships among controls compared to high-density microarray datasets. To address this issue, we developed a new method to identify and mask genomic regions with excess IBD. This method, implemented in ERSA 2.0, fully resolved the inflated cryptic relationship detection rates while improving relationship estimation accuracy. ERSA 2.0 detected all 1(st) through 6(th) degree relationships, and 55% of 9(th) through 11(th) degree relationships in the 30 families. We estimate that WGS data provides a 5% to 15% increase in relationship detection power relative to high-density microarray data for distant relationships. Our results identify regions of the genome that are highly problematic for IBD mapping and introduce new software to accurately detect 1(st) through 9(th) degree relationships from whole-genome sequence data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose of Review
Biliary atresia is a serious neonatal liver disease due to obstructed bile ducts that has better outcomes when detected and treated in the first 30–45 days of life. This review ...examines different methods to screen newborns for biliary atresia as well as discusses observations from ongoing screening programs implemented in parts of the United States.
Recent Findings
Screening strategies for biliary atresia include detecting persistent jaundice, examining stool color, testing fractionated bilirubin levels, or measuring bile acid levels from dried blood spot cards. The stool color card program is the most widely used screening strategy worldwide. An alternative approach under investigation in the United States measures fractionated bilirubin levels, which are abnormal in newborns with biliary atresia. Fractionated bilirubin screening programs require laboratories to derive reference ranges, nurseries to implement universal testing, and healthcare systems to develop infrastructure that identifies and acts upon abnormal results.
Summary
Biliary atresia meets the disease-specific criteria for newborn screening. Current studies focus on developing a strategy which also meets all test-specific criteria. Such a strategy, if implemented uniformly, has the potential to accelerate treatment and reduce biliary atresia’s large liver transplant burden.
Abstract Diagnostic delay remains a barrier to improving biliary atresia (BA) outcomes. We tested the implementation feasibility of a two stage BA newborn screening program in an integrated ...healthcare system. Methods Under a waiver of consent, we measured direct bilirubin (DB) levels in well newborns undergoing standard of care hyperbilirubinemia screening at four hospitals. Initial DB was measured by modifying nursery admission electronic medical record (EMR) order sets. Second‐stage DB was obtained at ~2 weeks of age under parental permission/informed consent (PP/IC). Implementation measures included the proportions of (1) eligible newborns that were screened before nursery discharge, (2) newborns undergoing second stage screening at ~2 weeks of age, and (3) newborns that underwent clinical evaluation for persistently elevated DB. Results A total of 12,276 newborns met eligibility criteria for screening, of which 12,055 (98.2%) underwent first‐stage screening in the newborn nursery. Ninety‐four (0.78%) had elevated positive initial screens. Ninety newborns (95.7%) underwent second‐stage screening ( n = 20) or contact was made with the primary care provider to recommend second‐stage screening ( n = 70). Among all screened newborns, 15 (0.12%) had abnormal second screens. All had follow‐up clinical evaluation for potential cholestatic liver disease. No BA cases were identified through screening, though two infants who met exclusion criteria (admission to the newborn intensive care unit) were subsequently diagnosed with BA during the screening period. Conclusions BA newborn screening is feasible in an integrated health network. Low consent rates have implications for future studies. Program infrastructure is required for implementation success and sustainability.
What is Known Diagnostic delay remains a barrier to improving biliary atresia (BA) outcomes. Newborn screening reduces diagnostic delay and may improve BA outcomes. Whether newborn screening can be implemented broadly is unknown. What is New BA newborn screening is feasible in an integrated healthcare network and such a network may be an ideal setting to study effectiveness, cost‐effectiveness, and potential for harm. BA newborn screening requires infrastructure for success and sustainability. Low consent rates may impact the design of future studies.
We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor-negative polyarticular ...JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10(-8)) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10(-6)). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10(-6)) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
BACKGROUND/RATIONALE:Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy ...(KPE), BA leads to death or liver transplant (LTx). Early-onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver prognostication.
RESULTS:We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be girls with a significantly different mean bilirubin (P = 0.002), albumin (P = 0.001), and alanine aminotransferase (P = 0.03) at 3 months post-KPE. By 1 year post-KPE, 50% of patients in the high CHP intensity group required LTx versus 27% in the low CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than 3 times the risk of requiring LTx by 4 years of age (hazard ratio 3.6, 95% confidence interval 1.15–10.93, P = 0.03). When controlling for sex and total bilirubin >2 mg/dL and albumin at 3 months post-KPE, it predicted nearly 7 times the risk of LTx (hazard ratio 6.89, 95% confidence interval 1.38–34.32, P = 0.02).
CONCLUSION:Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.
High-throughput sequencing of related individuals has become an important tool for studying human disease. However, owing to technical complexity and lack of available tools, most pedigree-based ...sequencing studies rely on an ad hoc combination of suboptimal analyses. Here we present pedigree-VAAST (pVAAST), a disease-gene identification tool designed for high-throughput sequence data in pedigrees. pVAAST uses a sequence-based model to perform variant and gene-based linkage analysis. Linkage information is then combined with functional prediction and rare variant case-control association information in a unified statistical framework. pVAAST outperformed linkage and rare-variant association tests in simulations and identified disease-causing genes from whole-genome sequence data in three human pedigrees with dominant, recessive and de novo inheritance patterns. The approach is robust to incomplete penetrance and locus heterogeneity and is applicable to a wide variety of genetic traits. pVAAST maintains high power across studies of monogenic, high-penetrance phenotypes in a single pedigree to highly polygenic, common phenotypes involving hundreds of pedigrees.
Background & Aims Standard therapy for children newly diagnosed with Crohn's disease (CD) includes early administration of immunomodulators after initial treatment with corticosteroids. We compared ...the effectiveness of early (≤3 mo after diagnosis) treatment with an anti-tumor necrosis factor (TNF)α with that of an immunomodulator in attaining clinical remission and facilitating growth of pediatric patients. Methods We analyzed data from the RISK study, an observational research program that enrolled patients younger than age 17 diagnosed with inflammatory (nonpenetrating, nonstricturing) CD from 2008 through 2012 at 28 pediatric gastroenterology centers in North America. Patients were managed by physician dictate. From 552 children (median age, 11.8 y; 61% male; 63% with pediatric CD activity index scores >30; and median C-reactive protein level 5.6-fold the upper limit of normal), we used propensity score methodology to identify 68 triads of patients matched for baseline characteristics who were treated with early anti-TNFα therapy, early immunomodulator, or no early immunotherapy. We evaluated relationships among therapies, corticosteroid and surgery-free remission (pediatric CD activity index scores, ≤10), and growth at 1 year for 204 children. Treatment after 3 months was a covariate. Results Early treatment with anti-TNFα was superior to early treatment with an immunomodulator (85.3% vs 60.3% in remission; relative risk, 1.41; 95% confidence interval CI, 1.14-1.75; P = .0017), whereas early immunomodulator therapy was no different than no early immunotherapy (60.3% vs 54.4% in remission; relative risk, 1.11; 95% CI, 0.83-1.48; P = .49) in achieving remission at 1 year. Accounting for therapy after 3 months, early treatment with anti-TNFα remained superior to early treatment with an immunomodulator (relative risk, 1.51; 95% CI, 1.20-1.89; P = .0004), whereas early immunomodulator therapy was no different than no early immunotherapy (relative risk, 1.00; 95% CI, 0.75-1.34; P = .99). The mean height z-score increased compared with baseline only in the early anti-TNFα group. Conclusions In children newly diagnosed with comparably severe CD, early monotherapy with anti-TNFα produced better overall clinical and growth outcomes at 1 year than early monotherapy with an immunomodulator. Further data will be required to best identify children most likely to benefit from early treatment with anti-TNFα therapy.
Background and Aims
Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these ...medications improve outcomes.
Approach and Results
We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty‐four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention‐to‐treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma‐glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant NS), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5‐year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis.
Conclusions
We presented the largest‐ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end‐stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo‐controlled treatment trials are needed to identify effective treatments for pediatric PSC.
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