Software as a Service for the Genomic Prediction of Complex Diseases
Authors: Bolli Alessandro , Di Domenico Paolo , Bottà Giordano 
Published: September 2019

In the last decade the scientific community witnessed a large increase in Genome-Wide Association Study sample size, in the availability of large Biobanks and in the improvements of statistical methods to model genomes features. This have paved the way for the development of new prediction medicine tools that use genomic data to estimate disease risk. One of these tools is the Polygenic Risk Score (PRS), a metric that estimates the genetic risk of an individual to develop a disease, based on a combination of a large number of genetic variants.

Using the largest prospective genotyped cohort available to date, the UK Biobank, we built a new PRS for Coronary Artery Disease (CAD) and assessed its predictive performances along with two additional PRS for Breast Cancer (BC), and Prostate Cancer (PC). When compared with previously published PRS, the newly developed PRS for CAD displayed higher AUC and positive predictive value. PRSs were able to stratify disease risks from 1.34% to 25.7% (CAD in men), from 0.26% to 8.62% (CAD in women), from 1.6% to 24.6% (BC), and from 1.4% to 24.3% (PC) in the lowest and highest percentiles, respectively. Additionally, the three PRSs were able to identify the 5% of the UK Biobank population with a relative risk for the diseases at least 3 times higher than the average.

Family history is a well recognised risk factor of CAD, BC, and PC and it is currently used to identify individuals at high risk of developing the diseases. We show that individuals with family history can have completely different disease risks based on PRS stratification: from 2.1% to 33% (CAD in men), from 0.56% to 10% (CAD in women), from 2.3% to 35.8% (BC), and from 1.0% to 34.0% (PC) in the lowest and highest percentiles, respectively. Additionally, the PRSs demonstrated higher predictive performance (AUCs (including age) CAD: 0.81, PC: 0.80, and BC: 0.68) than family history (AUCs (including age) CAD: 0.79, PC: 0.73, and BC: 0.61) in predicting the onset of diseases.

Hyperlipidemia is well known to be associated with higher CAD risk, but a predictive performance comparison between each lipoprotein and CAD PRS has never been assessed. PRS shows higher discrimination capacity and Odds ratio per Standard deviation than LDL, HDL, total cholesterol-HDL ratio, ApoA, ApoB, ApoB-ApoA ratio, and Lipoprotein(a). Comparing the empirical risk distribution between PRS and each lipoprotein, we show that lipoprotein thresholds, currently used in clinical practice, identify a population equal to or smaller than what can be identified with the PRS at the same CAD risk threshold. Moreover, there is not correlation (max ρ: 0.137) between PRS and each lipoprotein, indicating that PRS captures different component of CAD etiology and identifies different people at high risk than those identified by lipoproteins, demonstrating to be an invaluable tool in CAD prevention.

One of the major impairment of the PRS usage in clinical practice is the computational complexity needed to calculate per-individual PRSs. Deep bioinformatics expertise is required to run the entire pipeline, from imputing genomic data, through quality control to result visualisation. For these reasons we developed a Software as a Service (SaaS) for genomic risk prediction of complex diseases. The SaaS is fully automated, GDPR complaint and has been certified as a CE marked medical device. We made the SaaS freely available for research purposes. Researchers willing to use the SaaS can contact research@genomicriskscore.io