ORCID Profile
0000-0002-4089-7399
Current Organisation
University of California, San Diego
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Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2019
DOI: 10.1101/679092
Abstract: We aimed to determine the effect of s le size on performance of polygenic hazard score (PHS) models in predicting the age at onset of 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 (34,444 s les) and testing (6,417 s les) sets. Two PHS model-building strategies were investigated. Established-SNP model considered 65 SNPs that had been associated with prostate cancer in the literature. A stepwise SNP selection was used to develop Discovery-SNP models. The performance of each PHS model was calculated for random sizes of the training set (1 to 30 thousand). The performance of a representative Established-SNP model was estimated for random sizes of the testing set (0.5 to 6 thousand). Mean HR 98/50 (hazard ratio of top 2% to the average in the 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 s les was increased from 1 to 30 thousand. The 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 s le sizes of 0.6 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 to 30 thousand men is required to develop Discovery-SNP PHS models for prostate cancer. The required s le size could be reduced to 10 thousand s les, if a set of SNPs associated with the disease has already been established. Polygenic hazard scores represent a recent advancement in polygenic prediction to model the age of onset of various diseases, such as Alzheimer’s disease or prostate cancer. These scores accumulate small effect sizes from several tens of genetic variants and can be used to establish an in idual’s risk of experiencing an event relative to a control population across time. The largest barrier to the development of polygenic hazard scores is the large number of study subjects needed to develop the underlying models. We sought to understand the effect of varying the total number of s les on the performance of a polygenic hazard score in the context of prostate cancer. We found that the performance of the score did not appreciably change beyond 20 to 30 thousand observations when developing the model from scratch. However, when the discovery of the genetic variants can be borrowed from those already identified in the literature to be associated with the disease, the required number of s les is reduced to 10 thousand with no appreciable detriment in performance. We hope that these results can guide the design of future studies of polygenic scores in other diseases and demonstrate the importance of genome-wide association studies.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2020
DOI: 10.1158/1055-9965.EPI-19-1527
Abstract: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3–T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. PHS provides in idualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. Personalized genetic risk assessments could inform prostate cancer screening decisions.
Publisher: BMJ
Date: 10-01-2018
DOI: 10.1136/BMJ.J5757
Abstract: To 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. Analysis 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 in idual 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. Multiple institutions that were members of international PRACTICAL consortium. All 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. Prediction with hazard score of age of onset of aggressive cancer in validation set. In 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 Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2020
Publisher: Springer Science and Business Media LLC
Date: 12-02-2022
DOI: 10.1038/S41391-022-00497-7
Abstract: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for ex le, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43–15.16] in ProtecT, 7.07 [6.58–7.60] in African ancestry, 10.31 [9.58–11.11] in Asian ancestry, and 11.18 [10.34–12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11–0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15–0.22) and 0.26 (0.19–0.33), respectively. We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in erse populations.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2021
Publisher: Springer Science and Business Media LLC
Date: 23-02-2021
DOI: 10.1038/S41467-021-21287-0
Abstract: Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS 1 ) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS 2 (PHS 1 , adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS 2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p 10 −180 ). Comparing the 80 th /20 th PHS 2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS 2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
Publisher: Cold Spring Harbor Laboratory
Date: 18-08-2021
DOI: 10.1101/2021.08.14.21261931
Abstract: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry—the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for ex le, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in erse populations.
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Tyler Seibert.