The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis.

UNLABELLED: The biochemical response to ursodeoxycholic acid (UDCA)--so-called "treatment response"--strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). CONCLUSIONS: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care.

Quantitative linkage analysis for pancreatic B-cell function and insulin resistance in a large twin cohort.

OBJECTIVE: Insulin resistance and disturbed glucose homeostasis are key characteristics of metabolic syndrome, diabetes, and cardiovascular disease. The recent nonlinear computer version of homeostasis model assessment (HOMA)2 provides an appropriate and convenient assessment of glucose metabolism, enabling gene-mapping studies in large population samples. RESEARCH DESIGN AND METHODS: Fasting insulin and glucose concentration were measured in 758 dizygous and 305 monozygous nondiabetic female pairs from the St. Thomas' U.K. adult twin registry (TwinsUK). Insulin resistance (IR) and pancreatic beta-cell function (BCF) were estimated from this data using the HOMA2 model. RESULTS: Genome-wide variance component linkage analysis using 2,231 genetic markers identified a highly significant quantitative trait locus for BCF on chromosome 10p15 (logarithm of odds [LOD] 6.2, P = 0.0001), a region recently shown to contain a functional variant for type 1 diabetes. Both BCF and IR suggested a pleiotropic effect on 17q25 (univariate LOD 3.2, P = 0.0012, and 2.38, P = 0.0087; bivariate LOD 2.66), and one additional region showed linkage for IR on chromosome 22q11 (LOD 3.2, P = 0.0016), providing replication and refining previous findings for diabetes and associated traits. CONCLUSIONS: To our best knowledge, this is the first genome-wide linkage screen for HOMA2 indexes in a large, healthy female sample. These results suggest that loci involved in control of normal glucose homeostasis among nondiabetic individuals might overlap with those involved in the development of diabetes. Linkage replications in independent studies and across populations provide information on important regions of common but potentially heterogeneous variability that can now be used for targeted positional candidate studies.