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The advent of genome-wide association studies (GWAS) has led to the discovery of common risk loci for the majority of common diseases. These discoveries raise the possibility of using these variants for risk prediction in a clinical setting.
GWAS
Genome-wide association studies (GWAS) are used to identify common genetic factors that influence health and disease. genetic predic-tion is improved via GWAS good genetic prediction of age-related macular degeneration was quickly enabled by mul-tiple largeeffect variants identified by GWAS Crohns disease, can be reasonably well predicted by a large number of weak effects. Note that the range of AUCs for these diseases is very similar to the range found in classical prediction
Assuming a breast cancer lifetime risk(k) of 12%, a BRCA1/2 penetrance of approximately 50%, and a frequency of around 1%, the AUC of BRCA1/2 testing would only be 0.52.
MODELLING CONCERNS
Accurate prediction is done if the genetic architecture of a disease were completely described.poor prediction is due to poor current understanding of the underlying genetics of a disease, whereas others might never be tractable to genetic prediction.
Three models have been proposed each of which corresponds to a dif-ferent assumption about the distribution of disease probability in the population log model:analytically tractable but relatively unrealistic, assuming that probabilities are log-normally distributed, which can create disease probabilities greater than 1
logistic model:odds ratios are log-normally distributed, probit (or liability threshold) model:assumes a continuous distri-bution of a disease phenotype (called the liability) in the population, with heritable and non-heritable components.
genetic risk predic-tion is highly stable over time, as a persons genetic sequence is essentially constant throughout their life. Cost effectiveness Attaching a patients genome to an electronic medical record will enable a variety of prediction scenarios depend-ent on disease aetiology, prevalence and prevention and treatment options
Genetic epidemiology:is the study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors.
established GWAS loci typically explain only a small fraction of the heritability of complex diseases *an observation known as missing heritability+ It has been shown that 3% of variance (corresponding to an AUC of 0.65)in schizophrenia risk can be explained by a polygenic model, including a large number of loci that did not achieve genome-wide significance
ROC
Efectiveness of continuous diagnostic markers in distinguishing between diseased and healthy individuals A person is assessed as diseased (positive) or healthy (negative) depending on whether the corresponding marker value is greater than or less than or equal to a given threshold value. The theoretical ROC curve is a plot of q = sensitivity versus p =1-specicity for all possible threshold values
AUC
Let X and Y denote the diagnostic marker measurements for diseased and healthy subjects, respectively. Bamber showed that AUC= Prob (X>Y). This can be in-terpreted as the probability that in a randomly selected pair of healthy and diseased individuals the diagnostic marker value is higher for the diseased subject. Values of AUC close to 1.0 indicate that the marker has high diagnostic accuracy. global index of diagnostic accuracy general measure for the diferences between two distributions
Log-normal distribution
In probability theory, a log-normal distribution is a continuous probability distribution of a random variable whose logarithm is normally distributed. If X is a random variable with a normal distribution, then Y = exp(X) has a log-normal distribution; likewise, if Y is log-normally distributed, then X = log(Y) is normally distributed.