The NIH Pharmacogenetics Research Network (PGRN) was conceived to enable formation of a series of multi-disciplinary research groups funded to conduct studies addressing research problems in pharmacogenetics. These groups were united by the purpose of developing and populating a public database, which was envisioned as a tool for all researchers in the field. Funding of these awards began in 2000 and 2001. The investigators are “driven by the science,” and outside consultants who made recommendations in 2003 have stated that the network should strive to become “more than the sum of the parts.” Therefore, in anticipation of the steps to be taken by the PGRN to maximize its potential, NIH wants to clarify and amplify its goals.
The paramount aims of the network remain to:
1) perform the highest quality research studies to correlate drug response phenotypes with genetic variation
2) create a valuable knowledge base (PharmGKB) populated with reliable information that links phenotypes to genotypes
3) become an interactive network of investigators that impacts and elevates the field of pharmacogenetics with knowledge, tools, and resources
This is even more true in 2003 with completion of the Human Genome Project, with an ever-accumulating body of information on the importance of human genetic variation, as well as recently-initiated studies of the structure of variation with the HapMap project. While broadly-based and unbiased genomic information is desired, the field of pharmacogenetics offers a test bed for delving deeply into selected families of proteins and genes. The PGRN researchers are poised to contribute to the interpretation and application of this knowledge to human health.
Specifically, NIH wants to reinforce that the goals of the PGRN, in addition to the traditional measures of the highest quality research studies (e.g., peer-reviewed individual publications), include expectations of the following:
To build the knowledge base PharmGKB, with accurate and detailed definitions of genotypes and phenotypes in pharmacogenetics
- Datasets & Database – generate data for deposition and dissemination
- reference sequence and variant data, with population frequencies
- efficient yet complete definitions of phenotypes in pharmacogenetics
- statistically valid phenotype-genotype correlations
- representation of mechanistic understanding vs. statistical association
- dissection and analysis of complex drug responses
- defined categories of phenotypic knowledge
- descriptions of clinical impact
- in vitro and in vivo assay comparisons
- careful and complete annotation of methods
- user-friendly representation for phenotype-genotype correlations
- clickable displays of genetic/genomic information
- visual depiction of pathways
- infrastructure that is standards-based
- technically sound database design
(evaluation criteria: what is the quality and quantity of the data types deposited into PharmGKB? who uses the datasets, and how are they used? are the displays intuitive and helpful for database use?)
To produce shared resources, on a realistic and defined timetable, to be shared rapidly and without restrictions
- Computational Tools – for distribution with instructions for appropriate usage
- software programs useful for pharmacogenetics researchers (e.g. haplotyping, linkage equilibrium, recombination, population genetics statistics)
- programs with standardized descriptors for systematic phenotypic data collection
- computational models for knowledge domains (e.g. pharmacokinetics)
- analytic tools to identify gene x drug interactions
- Experimental Tools – created with intent to share with the research community
- model animals and organisms useful for comparative purposes
- in vitro engineered cellular expression systems
- chips & platforms useful for drug response testing and prediction
- Reagents – for distribution at modest and appropriate costs
- clones (genomic and cDNA), and primers
- antibodies for protein detection
- sequences found to successfully manipulate expression
- cell lines and tissue samples useful for pharmacogenetics studies
- sample sets from reference populations, appropriately consented & deposited
(evaluation criteria: what is the amount and value of the tools produced? have these materials/programs been requested and employed by others?)
To advance the research as a network, to work to define common goals and needs, and to solve problems
- Collaborations – maximize scientific impact and accelerate progress
- among PGRN groups to share methodological and technical expertise
- among PGRN groups to enhance study power in scientific and disease areas
- with outside networks to offer pharmacogenetics analysis skill sets
- standardized protocols for measuring drug responses (e.g. pharmacodynamics)
- where appropriate, to contribute to pre-industrial drug development
- Study Designs – debate and compare, validate different designs
- develop statistical approaches to efficient sample use and analysis
- define power and size requirements for pharmacogenetics studies
- build well-described patient cohorts of sufficient size
- contrast study design theories, for high and low frequency variants
- set standards for gene re-sequencing depth, e.g. coverage of flanking regions
- set definitions useful and compatible for research, industry, and FDA
- Technologies – seek and employ state-of-the art developments
- compare array platforms for pharmacogenetics studies
- test, pilot, and evaluate other new/upcoming methodologies
(evaluation criteria: what recommendations have resulted from network discussions? have these led to scientific interactions? are there joint contributions and/or publications?)
To communicate as a network with other scientists, both within and outside the field, and with non-scientists
- Information – communicate with the pharmacogenetics user communities
- inform other scientists of PGRN studies, ongoing and planned
- create a literature archive of highest quality pharmacogenetics studies
- organize scientific meetings as stand-alone gatherings and at national meetings
- promote the best ethical practices for pharmacogenetics research scientists
- explain purposes of PGRN research to lay people arriving at web sites
(evaluation criteria: who is attending scientific meetings? has the literature content been accessed and utilized appropriately? what “hits” have occurred on which areas of the web site?)
PGRN members are charged with inventorying their assets and expertise, and prioritizing their collective efforts. They should identify their strengths, and plan to share data, reagents, tools and study designs. They need to take advantage of new technologies, and communicate plans with the scientific public. Their intellectual policy practices must promote research and yet allow commercialization.
The PGRN members should identify future opportunities to the NIH, and gaps in existing studies that need to be addressed. They should be willing to consider redistributing a portion of their own resources where new approaches can be test-bedded in the network. The PGRN offers extraordinary intellectual power, and must make a major impact by utilizing the network’s research knowledge to discover and articulate fundamental principles common to pharmacogenetics studies.
NIH expects the PGRN to develop a strategic plan of action to guide its future efforts, which will specifically identify the details of what it can offer in the next two years, along with a realistic timetable to achieve those goals and measure the accomplishments. This document and that action plan will be shared with an External Scientific Panel, for the purpose of exchanging ideas and periodically evaluating progress towards the NIH’s and the PGRN’s goals.
Revised 6/11/03 -- with comments incorporated from NIGMS, NHLBI, NCI, NCBI, NHGRI, NIEHS, the PGRN Coordinating Committee and the PGRN PIs.