PMC:6323553 / 17090-19951 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6323553","sourcedb":"PMC","sourceid":"6323553","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6323553","text":"Optimizing the PRS for Prediction of Subtype-Specific Disease\nFor evaluation of subtype-specific models following stepwise regression, SNP effect sizes were estimated, in the first instance, in each disease subtype. The best subtype-specific PRSs using this method were also obtained at a p value threshold of p \u003c 10−5 (Table S5). The 305-SNP PRS was supplemented with 6 additional SNPs associated with ER-positive at p value \u003c 10−6 and, in addition, by two known rare breast cancer susceptibility variants in the BRCA2 and CHEK2 genes, bringing the total number of SNPs included to 313 (PRS313).\nThe optimum subtype-specific PRS was obtained when a subset of these 313 SNPs (196 SNPs with a case-only p value for association with ER-negative versus ER-positive disease of p \u003c 0.025) were given subtype-specific weights, while the remaining SNPs were given overall breast cancer weights. For ER-negative disease, the OR improved from OR = 1.45 (95%CI: 1.35–1.56) to OR = 1.47 (95%CI: 1.37–1.58) using the hybrid method compared with using only subtype-specific estimates, while for ER-positive disease the results were similar (OR = 1.74) (Tables S6 and S7).\nSubtype-specific prediction using the lasso analysis was optimized using case-only lasso analysis. The OR per 1 SD in the validation set was 1.81 (95%CI: 1.73–1.89) for ER-positive and 1.48 (95%CI: 1.37–1.59) for ER-negative disease (Tables 2 and S8).\nTable 2 Association between PRS and Breast Cancer Risk in the Validation Set and Prospective Test Datasets\nValidation Set Prospective Test Set\nORa 95% CI AUC ORa 95% CI AUC\n77 SNP PRS (PRS77)\nOverall BC 1.49 1.44–1.56 0.612 1.46 1.42–1.49 0.603\nER-positive 1.56 1.49–1.63 0.623 1.52 1.48–1.56 0.615\nER-negative 1.40 1.30–1.50 0.596 1.35 1.27–1.43 0.584\n313 SNP PRS (PRS313)\nOverall BC 1.65 1.59–1.72 0.639 1.61 1.57–1.65 0.630\nER-positive 1.74 1.66–1.82 0.651 1.68 1.63–1.73 0.641\nER-negative 1.47 1.37–1.58 0.611 1.45 1.37–1.53 0.601\n3,820 SNP PRS (PRS3820)\nOverall BC 1.71 1.64–1.79 0.646 1.66 1.61–1.70 0.636\nER-positive 1.81 1.73–1.89 0.659 1.73 1.68–1.78 0.647\nER-negative 1.48 1.37–1.59 0.611 1.44 1.36–1.53 0.600\nParameter selection and effect size estimation for derivation of the PRS was carried out in the training set as described in the Material and Methods. The optimal subtype-specific PRS was obtained by carrying out case-only logistic regression and estimating effect sizes in the relevant subtype for SNPs passing a p value of 0.025 in case-only ordinary logistic regression (ER-positive versus ER-negative disease). OR for association with breast cancer in the validation set derived using logistic regression adjusting for country and ten PCs. AUCs were adjusted for by country. In the prospective test set, logistic regression models were adjusted for study and 15 PCs. AUCs were adjusted for by study.\na OR per 1 SD for the PRS.","divisions":[{"label":"title","span":{"begin":0,"end":61}},{"label":"p","span":{"begin":62,"end":596}},{"label":"p","span":{"begin":597,"end":1158}},{"label":"label","span":{"begin":1411,"end":1418}},{"label":"caption","span":{"begin":1419,"end":1517}},{"label":"p","span":{"begin":1419,"end":1517}},{"label":"table","span":{"begin":1518,"end":2130}},{"label":"tr","span":{"begin":1518,"end":1553}},{"label":"th","span":{"begin":1518,"end":1532}},{"label":"th","span":{"begin":1533,"end":1553}},{"label":"tr","span":{"begin":1554,"end":1583}},{"label":"th","span":{"begin":1554,"end":1557}},{"label":"th","span":{"begin":1558,"end":1564}},{"label":"th","span":{"begin":1565,"end":1568}},{"label":"th","span":{"begin":1569,"end":1572}},{"label":"th","span":{"begin":1573,"end":1579}},{"label":"th","span":{"begin":1580,"end":1583}},{"label":"tr","span":{"begin":1584,"end":1602}},{"label":"td","span":{"begin":1584,"end":1602}},{"label":"tr","span":{"begin":1603,"end":1655}},{"label":"td","span":{"begin":1603,"end":1613}},{"label":"td","span":{"begin":1614,"end":1618}},{"label":"td","span":{"begin":1619,"end":1628}},{"label":"td","span":{"begin":1629,"end":1634}},{"label":"td","span":{"begin":1635,"end":1639}},{"label":"td","span":{"begin":1640,"end":1649}},{"label":"td","span":{"begin":1650,"end":1655}},{"label":"tr","span":{"begin":1656,"end":1709}},{"label":"td","span":{"begin":1656,"end":1667}},{"label":"td","span":{"begin":1668,"end":1672}},{"label":"td","span":{"begin":1673,"end":1682}},{"label":"td","span":{"begin":1683,"end":1688}},{"label":"td","span":{"begin":1689,"end":1693}},{"label":"td","span":{"begin":1694,"end":1703}},{"label":"td","span":{"begin":1704,"end":1709}},{"label":"tr","span":{"begin":1710,"end":1763}},{"label":"td","span":{"begin":1710,"end":1721}},{"label":"td","span":{"begin":1722,"end":1726}},{"label":"td","span":{"begin":1727,"end":1736}},{"label":"td","span":{"begin":1737,"end":1742}},{"label":"td","span":{"begin":1743,"end":1747}},{"label":"td","span":{"begin":1748,"end":1757}},{"label":"td","span":{"begin":1758,"end":1763}},{"label":"tr","span":{"begin":1764,"end":1784}},{"label":"td","span":{"begin":1764,"end":1784}},{"label":"tr","span":{"begin":1785,"end":1837}},{"label":"td","span":{"begin":1785,"end":1795}},{"label":"td","span":{"begin":1796,"end":1800}},{"label":"td","span":{"begin":1801,"end":1810}},{"label":"td","span":{"begin":1811,"end":1816}},{"label":"td","span":{"begin":1817,"end":1821}},{"label":"td","span":{"begin":1822,"end":1831}},{"label":"td","span":{"begin":1832,"end":1837}},{"label":"tr","span":{"begin":1838,"end":1891}},{"label":"td","span":{"begin":1838,"end":1849}},{"label":"td","span":{"begin":1850,"end":1854}},{"label":"td","span":{"begin":1855,"end":1864}},{"label":"td","span":{"begin":1865,"end":1870}},{"label":"td","span":{"begin":1871,"end":1875}},{"label":"td","span":{"begin":1876,"end":1885}},{"label":"td","span":{"begin":1886,"end":1891}},{"label":"tr","span":{"begin":1892,"end":1945}},{"label":"td","span":{"begin":1892,"end":1903}},{"label":"td","span":{"begin":1904,"end":1908}},{"label":"td","span":{"begin":1909,"end":1918}},{"label":"td","span":{"begin":1919,"end":1924}},{"label":"td","span":{"begin":1925,"end":1929}},{"label":"td","span":{"begin":1930,"end":1939}},{"label":"td","span":{"begin":1940,"end":1945}},{"label":"tr","span":{"begin":1946,"end":1969}},{"label":"td","span":{"begin":1946,"end":1969}},{"label":"tr","span":{"begin":1970,"end":2022}},{"label":"td","span":{"begin":1970,"end":1980}},{"label":"td","span":{"begin":1981,"end":1985}},{"label":"td","span":{"begin":1986,"end":1995}},{"label":"td","span":{"begin":1996,"end":2001}},{"label":"td","span":{"begin":2002,"end":2006}},{"label":"td","span":{"begin":2007,"end":2016}},{"label":"td","span":{"begin":2017,"end":2022}},{"label":"tr","span":{"begin":2023,"end":2076}},{"label":"td","span":{"begin":2023,"end":2034}},{"label":"td","span":{"begin":2035,"end":2039}},{"label":"td","span":{"begin":2040,"end":2049}},{"label":"td","span":{"begin":2050,"end":2055}},{"label":"td","span":{"begin":2056,"end":2060}},{"label":"td","span":{"begin":2061,"end":2070}},{"label":"td","span":{"begin":2071,"end":2076}},{"label":"tr","span":{"begin":2077,"end":2130}},{"label":"td","span":{"begin":2077,"end":2088}},{"label":"td","span":{"begin":2089,"end":2093}},{"label":"td","span":{"begin":2094,"end":2103}},{"label":"td","span":{"begin":2104,"end":2109}},{"label":"td","span":{"begin":2110,"end":2114}},{"label":"td","span":{"begin":2115,"end":2124}},{"label":"td","span":{"begin":2125,"end":2130}},{"label":"table-wrap-foot","span":{"begin":2131,"end":2834}},{"label":"footnote","span":{"begin":2131,"end":2834}},{"label":"p","span":{"begin":2131,"end":2834}},{"label":"label","span":{"begin":2835,"end":2836}}],"tracks":[]}