Dataset Information

The effect of sample size on polygenic hazard models for prostate cancer.

ABSTRACT: We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR_98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR_98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR_98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

SUBMITTER: Karunamuni RA

PROVIDER: S-EPMC7608255 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The effect of sample size on polygenic hazard models for prostate cancer.

Karunamuni Roshan A RA Huynh-Le Minh-Phuong MP Fan Chun C CC Eeles Rosalind A RA Easton Douglas F DF Kote-Jarai ZSofia Z Amin Al Olama Ali A Benlloch Garcia Sara S Muir Kenneth K Gronberg Henrik H Wiklund Fredrik F Aly Markus M Schleutker Johanna J Sipeky Csilla C Tammela Teuvo L J TLJ Nordestgaard Børge G BG Key Tim J TJ Travis Ruth C RC Neal David E DE Donovan Jenny L JL Hamdy Freddie C FC Pharoah Paul P Pashayan Nora N Khaw Kay-Tee KT Thibodeau Stephen N SN McDonnell Shannon K SK Schaid Daniel J DJ Maier Christiane C Vogel Walther W Luedeke Manuel M Herkommer Kathleen K Kibel Adam S AS Cybulski Cezary C Wokolorczyk Dominika D Kluzniak Wojciech W Cannon-Albright Lisa L Brenner Hermann H Schöttker Ben B Holleczek Bernd B Park Jong Y JY Sellers Thomas A TA Lin Hui-Yi HY Slavov Chavdar C Kaneva Radka R Mitev Vanio V Batra Jyotsna J Clements Judith A JA Spurdle Amanda A Teixeira Manuel R MR Paulo Paula P Maia Sofia S Pandha Hardev H Michael Agnieszka A Mills Ian G IG Andreassen Ole A OA Dale Anders M AM Seibert Tyler M TM

European journal of human genetics : EJHG 20200608 10

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated ...[more]

PMID: 32514134

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Project description:ObjectivesTo develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.DesignAnalysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.SettingMultiple institutions that were members of international PRACTICAL consortium.ParticipantsAll consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.Main outcome measuresPrediction with hazard score of age of onset of aggressive cancer in validation set.ResultsIn the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score.ConclusionsPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Dataset Information

The effect of sample size on polygenic hazard models for prostate cancer.

Publications

The effect of sample size on polygenic hazard models for prostate cancer.

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