Risk Prediction of Prostate Cancer with Single Nucleotide Polymorphisms and Prostate Specific Antigen

Purpose:Combined information on single nucleotide polymorphisms and prostate specific antigen offers opportunities to improve the performance of screening by risk stratification. We aimed to predict the risk of prostate cancer based on prostate specific antigen together with single nucleotide polymorphism information.Materials and Methods:We performed a prospective study of 20,575 men with prostate specific antigen testing and 4,967 with a polygenic risk score for prostate cancer based on 66 single nucleotide polymorphisms from the Finnish population based screening trial of prostate cancer and 5,269 samples of 7 single nucleotide polymorphisms from the Finnish prostate cancer DNA study. A Bayesian predictive model was built to estimate the risk of prostate cancer by sequentially combining genetic information with prostate specific antigen compared with prostate specific antigen alone in study subjects limited to those with prostate specific antigen 4 ng/ml or above.Results:The posterior odds of prostate cancer based on 7 single nucleotide polymorphisms together with the prostate specific antigen level ranged from 3.7 at 4 ng/ml, 14.2 at 6 and 40.7 at 8 to 98.2 at 10 ng/ml. The ROC AUC was elevated to 88.8% (95% CI 88.6-89.1) for prostate specific antigen combined with the risk score based on 7 single nucleotide polymorphisms compared with 70.1% (95% CI 69.6-70.7) for prostate specific antigen alone. It was further escalated to 96.7% (95% CI 96.5-96.9) when all prostate cancer susceptibility polygenes were combined.Conclusions:Expedient use of multiple genetic variants together with information on prostate specific antigen levels better predicts the risk of prostate cancer than prostate specific antigen alone and allows for higher prostate specific antigen cutoffs. Combined information also provides a basis for risk stratification which can be used to optimize the performance of prostate cancer screening.Peer reviewe

Assessing interactions of two loci (rs4242382 and rs10486567) in familial prostate cancer : statistical evaluation of epistasis

Understanding the impact of multiple genetic variants and their interactions on the disease penetrance of familial multiple prostate cancer is very relevant to the overall understanding of carcinogenesis. We assessed the joint effect of two loci on rs4242382 at 8q24 and rs10486567 at 7p15.2 to this end. We analyzed the data from a Finnish family-based genetic study, which was composed of 947 men including 228 cases in 75 families, to evaluate the respective effects of the two loci on the disease penetrance; in particular, the occurrence and number of prostate cancer cases within a family were utilized to evaluate the interactions between the two loci under the additive and multiplicative Poisson regression models. The risk alleles A at rs4242382 (OR = 1.14, 95% CI 1.08–1.19, P<0.0001) and a risk allele A at rs10486567 (OR = 1.06, 96%CI 1.01–1.11, P = 0.0208) were found to be associated with an increased risk of familial PrCa, especially with four or more cases within a family. A multiplicative model fitted the joint effect better than an additive model (likelihood ratio test X2 = 13.89, P<0.0001). The influence of the risk allele A at rs10486567 was higher in the presence of the risk allele A at rs4242382 (OR = 1.09 (1.01–1.18) vs. 1.01 (0.95–1.07)). Similar findings were observed in non-aggressive PrCa, but not in aggressive PrCa. We demonstrated that two loci (rs4242382 and rs10486567) are highly associated with familial multiple PrCa, and the gene-gene interaction or statistical epistasis was consistent with the Fisher's multiplicative model. These loci's association and epistasis were observed for non-aggressive but not for aggressive tumors. The proposed statistical model can be further developed to accommodate multi-loci interactions to provide further insights into epistasis.Public Library of Science open acces

Risk Prediction of Prostate Cancer with Single Nucleotide Polymorphisms and Prostate Specific Antigen

Purpose: Combined information on single nucleotide polymorphisms and prostate specific antigen offers opportunities to improve the performance of screening by risk stratification. We aimed to predict the risk of prostate cancer based on prostate specific antigen together with single nucleotide polymorphism information.Materials and Methods: We performed a prospective study of 20,575 men with prostate specific antigen testing and 4,967 with a polygenic risk score for prostate cancer based on 66 single nucleotide polymorphisms from the Finnish population based screening trial of prostate cancer and 5,269 samples of 7 single nucleotide polymorphisms from the Finnish prostate cancer DNA study. A Bayesian predictive model was built to estimate the risk of prostate cancer by sequentially combining genetic information with prostate specific antigen compared with prostate specific antigen alone in study subjects limited to those with prostate specific antigen 4 ng/ml or above.Results: The posterior odds of prostate cancer based on 7 single nucleotide polymorphisms together with the prostate specific antigen level ranged from 3.7 at 4 ng/ml, 14.2 at 6 and 40.7 at 8 to 98.2 at 10 ng/ml. The ROC AUC was elevated to 88.8% (95% CI 88.6–89.1) for prostate specific antigen combined with the risk score based on 7 single nucleotide polymorphisms compared with 70.1% (95% CI 69.6–70.7) for prostate specific antigen alone. It was further escalated to 96.7% (95% CI 96.5–96.9) when all prostate cancer susceptibility polygenes were combined.Conclusions: Expedient use of multiple genetic variants together with information on prostate specific antigen levels better predicts the risk of prostate cancer than prostate specific antigen alone and allows for higher prostate specific antigen cutoffs. Combined information also provides a basis for risk stratification which can be used to optimize the performance of prostate cancer screening. </p

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Probabilistic Cost-Effectiveness Analysis of Immunochemical Fecal Occult Blood Test for Colorectal Cancer Screening: Analysis of Data from Keelung Community-based Integrated Screening(KCIS)

背景 大腸直腸癌（Colorectal cancer ;CRC）篩檢一般使用傳統化學性糞便潛血法(Fecal Occult Blood Test; FOBT)，近年來免疫法興起許多人建議使用，但仍缺乏實證成本效益分析。而且影響篩檢成效因素尚包篩檢參與率及轉介順從率，這些因素會因為不同方法及個人特性的差異而有所不同。此外，成本計算上常會發生成本分布呈現偏態的問題及參數不確定性等問題，這些問題在族群決策分析上均扮演著重要的角色。 研究目的 本研究為隨機成本效益分析，主要目的包括四部份： 1. 利用社區族群篩檢實證資料探討社經人口學、生活型態、個人病史及家族病史等因素與大腸直腸腫瘤產生之相關性。 2. 利用社區族群進行免疫法糞便潛血檢查大腸直腸癌篩檢實證資料以探討人口學、生活型態、個人病史及家族病史如何影響第一次參檢率、再參檢率及轉介順從率。 3. 利用上述社區資料所得到大腸直腸癌個案探討使用二階段模式(two-stage model/hurdle model)調整偏態樣本分佈後，推估有關大腸直腸癌篩檢個案之疾病成本(Cost-of-Illness, COI)。 4. 利用上述1及2所得參數進行決定性及隨機機率模式針對不同間隔免疫法糞便潛血檢查、傳統化學法糞便潛血檢查及大腸直腸鏡檢之族群及個人層次之成本效益分析。 材料與方法 本研究用基隆市整合式篩檢1999-2004年間資料，將大腸直腸腺腫或癌之發生作為依變項，以人口學變項、生活型態、個人病史及家族病史等視為自變項，以Logistic regression function去探討發生大腸直腸腺腫或癌症之危險因子。此外，亦利用相同的自變項及分析方法，將篩檢率及轉介順從率視為依變項，探討其間的關係。最後將上述依個人特性去預到的發生腫瘤的危險性及參檢率、轉介順從率等應用於第四部分成本效益分析。 其次，由於篩檢大腸直腸癌個案成本含有設限及偏態的問題，本論文應用Hurdle model 進行成本的效正。 成本效益分析分別使用決定性模式及隨機模式。在隨機模式中使用貝氏隨機模式將相關參數依貝氏共軛對方式指定進行隨機成本效益分析，以計算增加成本效益比及達到成本效益機率之接受曲線。 主要研究結果 以決定模式作評估，並以社會的觀點來看時，相對於未篩檢，各項篩檢策略均具絕對之優勢，均為成本節約（cost-saving）的方案。所累積的淨效益以每十年一次大腸直腸鏡檢最多，為12.7993人年命，其次為每年一次免疫法的FOBT，可得12.7988人年。若比較各組之增加成本效果比(incremental cost-effectiveness ratio;ICER)時，則每年一次免疫法的FOBT為最佳策略。 同樣的方法進行次族群分析時，除50-59歲女性以外，其它的次族群均以每10年一次的大腸直腸鏡檢為最佳策略。 以個人的觀點評估55歲男性，在不同的大腸直腸的危險因子的影響下，具大腸直腸癌家族病史者之最佳策略為每10年做一次大腸直腸鏡檢；無家族史者則以每年做一次iFOBT為最佳篩檢策略。 當考慮到個人因素異質性，以隨機模式進行評估時以每10年一次的大腸直腸鏡檢具成本效益的機率最高，尤其是針對60-69歲男性而言。 結論 本研究應用隨機成本效益貝氏分析基隆地區以不同間隔提供免疫法糞便潛血以進行大腸直腸癌篩檢時發現，即使考慮二次不確定變異下，每年篩檢一次在族群層次上具成本效益。透過個人對大腸直腸癌的易感受性及參檢率與順從率等影響因素之探討，及修正成本偏態後，可顯示個人層次成本效益之結果，此種方法可應用於未列入國家篩檢政策之疾病。Background Chemical Fecal Occult Blood Test (FOBT) has been used to establish mass colorectal cancer (CRC) screening program traditionally. However, since Immunochemical FOBT has a higher predicting power, many people start to advocate using it for CRC screening. But so far there are not enough evidences to prove if it is cost-effectiveness. In addition, determinants of the effectiveness of screening also include attendance rate and compliance rate. Both of them will vary among people because of different personal characteristics. Besides, calculating cost often suffers the problems such as skewed data and uncertainty of parameters. Such problems play important roles for population decision-making. Research purpose This study was designed as a probabilistic cost-effectiveness analysis with four purposes: 1. To use community population screening data to investigate the association between covariates and tumor detected, those covariates including factors of socio-demographic, life style, personal disease history and family history. 2. To apply community population screening data to investigate the association between the attendance rate and referral rate and the same set of covariates used in 1. 3. To use cost data in community population screening to calculate the cost of illness of CRC. The Hurdle model was used to adjust the skewed cost. 4. To apply those parameters estimated above to establish deterministic and stochastic models, to compare different intervals of immunochemical FOBT screenings, and also for comparison the chemical FOBT and colonoscopy through cost-effectiveness analysis. Materials and methods The main data source is Keelung Community-based Integrated Screening (KCIS) data from 1999 to 2004.We investigated the association between colorectal tumor and a set of covariates, including socio-demography, life style, personal disease history and family history, through logistic regression function. Then we used the same method to predict compliance behavior. Finally, incorporating those parameters estimated by above methods into cost-effectiveness analysis. Besides, in order to account for censored and skewed cost problems in CRC screening, we adopted the Hurdle model to adjust the CRC medical cost. In terms of the analysis of cost-effectiveness, two approaches were used, namely deterministic and stochastic. In the stochastic model, Bayesian probabilistic estimation was used through Bayesian Conjugate distribution. The comparing indicators were incremental cost –effectiveness ratios (ICER) and acceptability curve. Results From a societal viewpoint through deterministic approach, comparing to no-screen, the other screening strategies are dominant and cost-saving. Discounted cumulative effectiveness shows colonoscopy every 10 years is the most-effective one, which will save 12.7993 life years. The following one is to have iFOBT (immunochemical Fecal Occult Blood Test) annually, which will save 12.7988 life years. Comparing the ICERs of all strategies to no-screen, iFOBT annually is the best strategy. Processing sub-groups analysis under the same approach, we found that undergoing colonoscopy every 10 years was the best strategy among all subgroups except the subgroup constituted of females aged 50-59. When evaluating males aged 55 affected by different risk factors of colorectal tumor, for those with family history of CRC, the best strategy is colonoscopy every 10 years. On the other hand, for those without family history of CRC, iFOBT annually is the best strategy. Taking personal heterogeneity into account, the economical evaluation through probabilistic model showed colonoscopy every 10 years is the best strategy, especially for the subgroup constituted of males aged 60-69. Conclusion This study applied Bayesian probabilistic cost-effectiveness to evaluate community-based CRC screening program by iFOBT. Under the consideration about second uncertainty, iFOBT annually shows cost-effectiveness on the population-level. Since we had been incorporated the covariates about personal susceptibility and compliance, and modified the skewed cost data, then we did the personal-level cost- effectiveness analysis. Such method could be applied to national screening policy for those diseases without any screening policy now.中文摘要 A-1 英文摘要 A-4 第一章 前言 1 第二章 文獻探討 5 第三章 材料與方法 32 第四章 結果 71 第五章 討論 122 第六章 結論 130 參考文獻 131 表目錄 Table 2.1 Characteristics of cost-effectiveness analyses of colorectal cancer screening 29 Table 3.1 Base case of parameters 65 Table 4.1 Demographic characteristics of target population 80 Table 4.2 Characteristic of KCIS attendee by first attending year 81 Table 4.3 Stage of screening detected cases, by screening round 85 Table 4.4 Logistic regression models for the association between first-round detected colorectal tumors and covariates 86 Table 4.5 Logistic regression models for the association between first-round detected CRC and covariates 88 Table 4.6 No. of attendee, positive finding, and referral by each screening year 90 Table 4.7 Logistic regression models for the association between participation (at least once attendance ) and relevant covariates 91 Table 4.8 Logistic regression models for the association between repeat(at least twice attendance ) and relevant covariates 94 Table 4.9 Logistic regression models for the association between referral and relevant covariates 97 Table 4.10 Mean cost estimated by Hurdle Model 100 Table 4.11 Incremental cost, effectiveness, and cost-effectiveness for the overall population 101 表目錄 Table 4.12 Incremental cost, effectiveness, and ICER compared to no screen, by age and gender 102 Table 4.13 Incremental cost, effectiveness, and ICER compared to iFOBT annually, by age and gender 105 Table 4.14 Incremental cost, effectiveness, and ICER for persons with different risks factors of CRC 107 Table 4.15 Distribution of incremental cost, effectiveness, and cost-effectiveness for the overall population 109 Table 4.16 Probability of cost-effectiveness under critical value of willingness to pay among strategies 110 Table 4.17 Probability of cost-effectiveness under critical value of willingness to pay among strategies for males aged 50-59 111 Table 4.18 Probability of cost-effectiveness under critical value of willingness to pay among strategies for females aged 50-59 112 Table 4.19 Probability of cost-effectiveness under critical value of willingness to pay among strategies for males aged 60-69 113 Table 4.20 Probability of cost-effectiveness under critical value of willingness to pay among strategies for females aged 60-69 114 Table 4.21 Probability of cost-effectiveness under critical value of willingness to pay among strategies for males aged 70-79 115 Table 4.22 Probability of cost-effectiveness under critical value of willingness to pay among strategies for females aged 70-79 11

Cost-Effectiveness Analysis of Personalized Hypertension Prevention

Background: While a population-wide strategy involving lifestyle changes and a high-risk strategy involving pharmacological interventions have been described, the recently proposed personalized medicine approach combining both strategies for the prevention of hypertension has increasingly gained attention. However, a cost-effectiveness analysis has been hardly addressed. This study was set out to build a Markov analytical decision model with a variety of prevention strategies in order to conduct an economic analysis for tailored preventative methods. Methods: The Markov decision model was used to perform an economic analysis of four preventative strategies: usual care, a population-based universal approach, a population-based high-risk approach, and a personalized strategy. In all decisions, the cohort in each prevention method was tracked throughout time to clarify the four-state model-based natural history of hypertension. Utilizing the Monte Carlo simulation, a probabilistic cost-effectiveness analysis was carried out. The incremental cost-effectiveness ratio was calculated to estimate the additional cost to save an additional life year. Results: The incremental cost-effectiveness ratios (ICER) for the personalized preventive strategy versus those for standard care were -USD 3317 per QALY gained, whereas they were, respectively, USD 120,781 and USD 53,223 per Quality-Adjusted Life Year (QALY) gained for the population-wide universal approach and the population-based high-risk approach. When the ceiling ratio of willingness to pay was USD 300,000, the probability of being cost-effective reached 74% for the universal approach and was almost certain for the personalized preventive strategy. The equivalent analysis for the personalized strategy against a general plan showed that the former was still cost-effective. Conclusions: To support a health economic decision model for the financial evaluation of hypertension preventative measures, a personalized four-state natural history of hypertension model was created. The personalized preventive treatment appeared more cost-effective than population-based conventional care. These findings are extremely valuable for making hypertension-based health decisions based on precise preventive medication

Personalized risk assessment for dynamic transition of gastric neoplasms

Abstract Background To develop an individually-tailored dynamic risk assessment model following a multistep, multifactorial process of the Correa’s gastric cancer model. Methods First, we estimated the state-to-state transition rates following Correa’s five-step carcinogenic model and assessed the effect of risk factors, including Helicobacter pylori infection, history of upper gastrointestinal disease, lifestyle, and dietary habits, on the step-by-step transition rates using data from a high-risk population in Matsu Islands, Taiwan. Second, we incorporated information on the gastric cancer carcinogenesis affected by genomic risk factors (including inherited susceptibility and irreversible genomic changes) based on literature to generate a genetic and epigenetic risk assessment model by using a simulated cohort identical to the Matsu population. The combination of conventional and genomic risk factors enables us to develop the personalized transition risk scores and composite scores. Results The state-by-state transition rates per year were 0.0053, 0.7523, 0.1750, and 0.0121 per year from normal mucosa to chronic active gastritis, chronic active gastritis to atrophic gastritis, atrophic gastritis to intestinal metaplasia, and intestinal metaplasia to gastric cancer, respectively. Compared with the median risk group, the most risky decile had a 5.22-fold risk of developing gastric cancer, and the least risky decile around one-twelfth of the risk. The median 10-year risk for gastric cancer incidence was 0.77%. The median lifetime risk for gastric cancer incidence was 5.43%. By decile, the 10-year risk ranged from 0.06 to 4.04% and the lifetime risk ranged from 0.42 to 21.04%. Conclusions We demonstrate how to develop a personalized dynamic risk assessment model with the underpinning of Correa’s cascade to stratify the population according to their risk for progression to gastric cancer. Such a risk assessment model not only facilitates the development of an individually-tailored preventive strategy with treatment for H. pylori infection and endoscopic screening but also provides short-term and long-term indicators to evaluate the program effectiveness