Hemophilia Inhibitor Genetics Study (HIGS)

A collaboration among scientists from academia, industry, and government

HIGS is a three-phase study designed to discover and confirm associations between genetic factors and the development of inhibitory antibodies to factor VIII. Phase I is a classical sib pair study enrolling two or more concordant affected sibs or discordant sibs and their parents. This phase was designed to discover linkage between markers and phenotypes. Phase II was designed to fine map chromosomal regions implicated in Phase I using a powerful analytical strategy, the Transmission Disequilibrium Test (TDT) developed by Robert Elston (1998). This test requires two parents and an affected offspring to test for distortions from expectations in the transmission of alleles from each heterozygous parent to the affected child. Phase III was planned as a replication and confirmatory step to validate single nucleotide polymorphism (SNP) associations observed in Phase I and Phase II in an unrelated cohort. This design is robust even for relatively small to modest effect genes that predispose to inhibitor development.

HIGS is a multicenter international study, with data and samples contributed by 28 countries in North America, Latin America, and Europe.

Since the start of HIGS, three events of direct impact to the project have occurred. First, genotyping costs have decreased considerably. Second, knowledge of the genome has expanded with the completion of the HapMap project, the annotation of the human genome, and the availability of both structural variation and single nucleotide polymorphisms in public databases. The third event was facilitated by a peer review conducted at the Laboratory of Genomic Diversity of the National Cancer Institute (NCI) in Frederick, MD, at the onset of the study (2003). With HIGS singled out as a well-designed study and a project of scientific significance by the NCI Board of Scientific Counselors, a successful (and unprecedented) argument was made to grant the study a special status, allowing HIGS, a commercially funded investigation, to take advantage of lower cost government rates for purchase of reagents and study materials, and gain access to laboratory testing platforms, equipment, and technical and scientific support at no cost to the study. The effect of these events has been to permit a powerful but affordable interim analysis.

Through collaboration with two other studies, the Hemophilia Growth and Development Study (HGDS) and the Malmö International Brother Study (MIBS), a combined cohort study group has been formed. DNA for members of the cohort is stored in the repository in Frederick, MD. Clinical and genetics data are stored and analyzed at Rho, Chapel Hill, NC.

For questions about this study, please contact Jennifer Waters at jwaters@rhoworld.com.

For more information about this research from ClinicalTrials.gov, please see below.

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