The exhaustive genomic scan approach, with an application to rare-variant association analysis

Region-based genome-wide scans are usually performed by use of a priori chosen analysis regions. Such an approach will likely miss the region comprising the strongest signal and, thus, may result in increased type II error rates and decreased power. Here, we propose a genomic exhaustive scan approach that analyzes all possible subsequences and does not rely on a prior definition of the analysis regions. As a prime instance, we present a computationally ultraefficient implementation using the rare-variant collapsing test for phenotypic association, the genomic exhaustive collapsing scan (GECS). Our implementation allows for the identification of regions comprising the strongest signals in large, genome-wide rare-variant association studies while controlling the family-wise error rate via permutation. Application of GECS to two genomic data sets revealed several novel significantly associated regions for age-related macular degeneration and for schizophrenia. Our approach also offers a high potential to improve genome-wide scans for selection, methylation, and other analyses

A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants.

In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of intravenously administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 days chronological age, an intravenous 3 hours infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiological safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 mug/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3F) with mean (range) PMA 27 weeks (26-29) and birth weight 1022 grams (810-1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/ml, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754-1182) ng/ml, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59-1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium and physiological safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated