Monday, 12 May 2014

Genome Studies offer low predictive value in detecting MS

Disanto G, Dobson R, Pakpoor J, Elangovan RI, Adiutori R, Kuhle J, Giovannoni G. The refinement of genetic predictors of multiple sclerosis. PLoS One. 2014 May 2;9(5):e96578. doi: 10.1371/journal.pone.0096578. eCollection 2014.

A recent genome wide association study (GWAS) demonstrated that more than 100 genetic variants influence the risk of multiple sclerosis (MS). We investigated what proportion of the general population can be considered at high genetic risk of MS, whether genetic information can be used to predict disease development and how the recently found genetic associations have influenced these estimates. We used summary statistics from GWAS in MS to estimate the distribution of risk within a large simulated general population. We profiled MS associated loci in 70 MS patients and 79 healthy controls (HC) and assessed their position within the distribution of risk in the simulated population. The predictive performance of a weighted genetic risk score (wGRS) on disease status was investigated using receiver operating characteristic statistics. When all known variants were considered, 40.8% of the general population was predicted to be at reduced risk, 49% at average, 6.9% at elevated and 3.3% at high risk of MS. Fifty percent of MS patients were at either reduced or average risk of disease. However, they showed a significantly higher wGRS than HC (median 13.47 vs 12.46, p = 4.08×10-10). The predictive performance of the model including all currently known MS associations (area under the curve = 79.7%, 95%CI = 72.4%-87.0%) was higher than that of models considering previously known associations. Despite this, considering the relatively low prevalence of MS, the positive predictive value was below 1%. The increasing number of known associated genetic variants is improving our ability to predict the development of MS. This is still unlikely to be clinically useful but a more complete understanding of the complexity underlying MS aetiology and the inclusion of environmental risk factors will aid future attempts of disease prediction




There are now 110 identified genetic variants which influence MS risk outside of the MHC (the “master switch” of the immune system). These genetic variants have been undoubtedly beneficial in helping us to understand the disease process underlying MS, and have implicated different aspects of the immune system. However, each variant is known to individually exert only a very small effect on MS risk, which raises the question of how helpful these genetic variants are in helping us to predict who is going to get MS?

Using statistical models incorporating these genetic variants, we tried to estimate what proportion of the general population is likely to be at a different MS risk compared to an average baseline risk. We found that about 90% of the general population are thought to be either at average or reduced risk of MS, with a higher than average risk in about 10%.
Further, when studying two groups of MS patients and healthy controls it was found that, based on their genetic make-up, more MSers were rated as having an increased or high MS risk compared to controls. However, more than half of MSers were still considered to be at average or reduced MS risk.

Overall, we found that as the numbers of known MS associated genetic variants have increased, so has our ability to predict MS. Nonetheless, this predictive ability is still poor and very unlikely to be useful clinically. Given that MS causation is influenced by both genetic and environmental risk factors, it will be important to determine how (and perhaps critically, when) these factors interact to influence MS risk in order to develop a more comprehensive, and accurate, model for MS prediction.  



CoI This work by TeamG

5 comments:

  1. You looked at 100 markers in 70 people? This is a highly underpowered study.

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    1. Look at the degree of overlap of the figure which is in the paper e.g. the right hand side. It is massive add a thousand more people and maybe the split will become more apparent, but with such overlap, would you have the confidence to predict person x had risk of MS verses being healthy maybe for a odd few people on the edges of the distribution.

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  2. with 100 different SNPs associated to MS there are 300 different genotypes- there should have been enough people in the study to assess with confidence the genotypic distribution of these 300 genotypes in MS patients and controls and then perform a risk assessment. The study was flawed from the start.

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62227-8/fulltext

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  3. Sounds like flogging a dead horse, the study of genetics of has not delivered any treatments for MS, or much insight into MS, we knew it was immune years ago

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