Friday, April 11, 2014

To Replicate or Not to Replicate

Dr. Aslibekyan and colleagues propose that an alternative to replication of genetic association studies be considered in an article titled “To Replicate or Not to Replicate: The Case of Pharmacogenetic Studies” in Circulation: Cardiovascular Genetics (2013).  It is understandable why replicating the positive results of a genetic association study is, as the authors state, “the gold standard” of validation. Replication is a useful tool to confirm the likelihood of an association from a previous genetic association study.

However, the results of genetic association studies, including genome wide association studies (GWAS), are often difficult to reproduce as evidenced in pharmacogenomics. The authors provide multiple reasons why false positives and false negatives in genetic association studies prevent results from being reproduced. Much of the data in pharmacogenomic studies come from groups of patients who may have differing drug regimens and intervention strategies. Other factors include low minor allele frequencies, small effect size of the variants, limited sample sizes, and differences in phenotype definitions.

The authors conclude that as an alternative to replication a combination of methods should be used to validate results. They’ve termed this multi-method validation of genetic association studies “triangulation”. They propose to validate results through a combination of functional validation in vitro and in animal models, joint analyses of several populations, and simulation-based methods, and cite a precedent for methodological triangulation in the social sciences. Social science research involves highly complex systems, and the inherent ethical limitations in human subjects research render reproducibility an impractical method of validation.

In a rebuttal, Dr. John Ioannidis argues that what pharmacogenetic association studies actually require are “better, more rigorous methods, and even more stringent replication, and clinical validation”. He proposes several strategies to yield better results from pharmacogenetic association studies including mining data from biobanks and electronic medical records, more stringent criteria for replication, improved methods of detecting and validating rare variants, focus on polygenic markers rather than on single genes, and validation with large, randomized clinical trials.

In a response, Dr. Aslibekyan and colleagues agreed with much of Dr. Ioannidis’ argument. They did, however, reiterate the concern that lowering P-value thresholds for single nucleotide variants could cause many single gene variants with true associations to be overlooked due to factors such as gene-environment interactions and epistasis.

Read the articles here:

To Replicate or Not to Replicate: the Case of Pharmacogenetic Studies: Establishing Validity of Pharmacogenomic Findings: From Replication to Triangulation. Circulation: Cardiovascular Genetics (2013)

To Replicate or Not to Replicate: the Case of Pharmacogenetic Studies: Have Pharmacogenomics Failed, or Do They Just Need Larger-Scale Evidence and More Replication? Circulation: Cardiovascular Genetics (2013)

PharmGKB Unaffected by the Heartbleed Bug

The "Heartbleed Bug" has been in the news a lot lately, and for good reason. It's a security vulnerability in some versions of OpenSSL that allows the theft of information that is protected, under normal conditions, by the SSL/TLS encryption used to secure the Internet. It's estimated that this has impacted about 30% of all websites. That's a lot of websites.

The good news for PharmGKB users is that our services were not affected by the bug. You do not have to change your password on PharmGKB.

If you're looking for a simple explanation of the problem, xkcd has the most concise one I've seen to date:

SLC22A1 VIP Summary Published in PG&G

Solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also called OCT1) is an important drug transporter mediating the hepatic uptake of many commonly used drugs. Several SLC22A1 variants have functional consequences and have been associated with altered disposition and response for drugs such as metformin, imatinib, sorafenib, tropisetron, morphine and tramadol.

We have published the
PharmGKB summary: very important pharmacogene information for SLC22A1 in the Pharmacogenetics and Genomics Journal.

Find out more...
View our SLC22A1 VIP on PharmGKB.

Read our new publication: 
PharmGKB summary: very important pharmacogene information for SLC22A1
Goswami S, Gong L, Giacomini K, Altman RB, Klein TE.
Pharmacogenet Genomics. 2014 Mar 27. [Epub ahead of print]

View all VIPs on PharmGKB.

Thursday, April 10, 2014

PharmGKB takes home Best Poster award at ISB 2014

PharmGKB is happy to announce that they were the recipients of the Best Poster award at the International Society for Biocuration conference in Toronto this week!

Russ Altman: Year In Review at AMIA Summit on Translational Bioinformatics 2014

Russ Altman presented the Year In Review yesterday at the AMIA Summit on Translational Bioinformatics 2014 in San Francisco.

Dr. Altman's year in review is meant as an overview for trends and publications for the previous year and to speculate about what opportunities might lie in the year ahead. He presented 32 publications (and 10 "shout outs") focused on translational bioinformatics in human biology.

The publications were organized into 8 topic areas:

  • Controversies
  • Clinical genomics
  • Drugs
  • Genetic basis of disease
  • Emerging data sources
  • Mice
  • Scientific process
  • Odds & Ends
The slides for Dr. Altman's presentation (as a PDF) have been posted to his blog:

Sunday, April 6, 2014

Biocuration 2014 Toronto

PharmGKB Scientific Curators Ellen McDonagh and Julia Barbarino are attending the Biocuration 2014 conference in Toronto.

On Monday 7th April, in a talk and poster presentation they will outline the PharmGKB curation process: how we curate PGx literature and interpret this for the clinic in the form of our Clinical Annotations

The conference will cover five main curation topics; clinical annotations, data integration and sharing, systems biology, functional annotations and microbial informatics.

Wednesday, March 26, 2014

Dr. Michelle Whirl-Carrillo promoted to Associate Director of PharmGKB

PharmGKB is delighted to announce the promotion of Dr. Michelle Whirl-Carrillo to Associate Director.

Dr. Whirl-Carrillo joined PharmGKB in 2002 as the project's first Scientific Curator. After briefly leaving PharmGKB to join the DTC genotyping start-up 23andMe, she returned in 2009 as the Assistant Director.

We congratulate Michelle on her achievement.