Rare variant association test with multiple phenotypes.

Although genome-wide association studies (GWAS) have now discovered thousands of genetic variants associated with common traits, such variants cannot explain the large degree of "missing heritability," likely due to rare variants. The advent of next generation sequencing technology has allowed rare variant detection and association with common traits, often by investigating specific genomic regions for rare variant effects on a trait. Although multiple correlated phenotypes are often concurrently observed in GWAS, most studies analyze only single phenotypes, which may lessen statistical power. To increase power, multivariate analyses, which consider correlations between multiple phenotypes, can be used. However, few existing multivariant analyses can identify rare variants for assessing multiple phenotypes. Here, we propose Multivariate Association Analysis using Score Statistics (MAAUSS), to identify rare variants associated with multiple phenotypes, based on the widely used sequence kernel association test (SKAT) for a single phenotype. We applied MAAUSS to whole exome sequencing (WES) data from a Korean population of 1,058 subjects to discover genes associated with multiple traits of liver function. We then assessed validation of those genes by a replication study, using an independent dataset of 3,445 individuals. Notably, we detected the gene ZNF620 among five significant genes. We then performed a simulation study to compare MAAUSS's performance with existing methods. Overall, MAAUSS successfully conserved type 1 error rates and in many cases had a higher power than the existing methods. This study illustrates a feasible and straightforward approach for identifying rare variants correlated with multiple phenotypes, with likely relevance to missing heritability.

Proposed Nomogram Predicting the Individual Risk of Malignancy in the Patients With Branch Duct Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVES: This study evaluated individual risks of malignancy and proposed a nomogram for predicting malignancy of branch duct type intraductal papillary mucinous neoplasms (BD-IPMNs) using the large database for IPMN. BACKGROUND: Although consensus guidelines list several malignancy predicting factors in patients with BD-IPMN, those variables have different predictability and individual quantitative prediction of malignancy risk is limited. METHODS: Clinicopathological factors predictive of malignancy were retrospectively analyzed in 2525 patients with biopsy proven BD-IPMN at 22 tertiary hospitals in Korea and Japan. The patients with main duct dilatation >10 mm and inaccurate information were excluded. RESULTS: The study cohort consisted of 2258 patients. Malignant IPMNs were defined as those with high grade dysplasia and associated invasive carcinoma. Of 2258 patients, 986 (43.7%) had low, 443 (19.6%) had intermediate, 398 (17.6%) had high grade dysplasia, and 431 (19.1%) had invasive carcinoma. To construct and validate the nomogram, patients were randomly allocated into training and validation sets, with fixed ratios of benign and malignant lesions. Multiple logistic regression analysis resulted in five variables (cyst size, duct dilatation, mural nodule, serum CA19-9, and CEA) being selected to construct the nomogram. In the validation set, this nomogram showed excellent discrimination power through a 1000 times bootstrapped calibration test. CONCLUSION: A nomogram predicting malignancy in patients with BD-IPMN was constructed using a logistic regression model. This nomogram may be useful in identifying patients at risk of malignancy and for selecting optimal treatment methods. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

Clinicopathological Meaning of Size of Main-Duct Dilatation in Intraductal Papillary Mucinous Neoplasm of Pancreas: Proposal of a Simplified Morphological Classification Based on the Investigation on the Size of Main Pancreatic Duct.

BACKGROUND: The 2012 consensus guideline on intraductal papillary mucinous neoplasm of the pancreas (IPMN) described a three-stage criteria involving main pancreatic duct (MPD) size with definitions of malignancy relevant for treatment decisions. Re-evaluation and simplification of this classification for clinicians are warranted. METHODS: Data from the Seoul National University Hospital of 375 consecutive patients with pathology-confirmed IPMN after surgery were analyzed. The association between clinicopathologic characteristics of IPMN and MPD size was assessed. The cut-off value of MPD size for a current definition of malignancy prediction was calculated. RESULTS: Diagnostic accuracy for malignancy was highest when the cut-off value of MPD size was 7 mm (area under the curve=0.7126). Dichotomizing IPMN into MPD≤7 mm versus MPD> mm, patient age (p=0.039), sex (p=0.001), presence of mural nodule (p<0.001), and invasiveness risk (13.2 vs. 39.8%, p<0.001) resulted in significantly different results. Mural nodule-negative patients with MPD>7 mm had a significantly lower 5-year survival rate than those with MPD≤7 mm (78.4 vs. 91.4%, p=0.006). Among patients with MPD size≤7 mm, elevated serum CA 19-9 and mural nodule were independent risk factors of malignancy. Patients with MPD size≤7 mm without these risk factors had malignancy risk of 2.6%. CONCLUSION: Using the definition of malignancy provided in the 2012 guideline, the MPD size> mm criterion was statistically driven. The current morphologic classification of IPMN can be simplified as branch-duct-predominant IPMN (MPD≤7 mm)' and main-duct-predominant IPMN (MPD> mm). Patients who are determined to have main-duct-predominant IPMN and branch-duct-predominant IPMN with elevated serum CA 19-9 or mural nodule are recommended to undergo surgical treatment.