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Genome-wide search for higher order epistasis as modifiers of treatment effects on bone mineral density in childhood cancer survivors.

ABSTRACT: Single-nucleotide polymorphisms (SNPs) contributing to interactions between regulatory elements that modulate gene transcription may explain some of the uncharacterized variation for complex traits. We explored this hypothesis among 856 adult survivors of pediatric cancer exposed to curative treatments that adversely affect bone mineral density (BMD). To restrict our search to interactions among SNPs in regulatory elements, our analysis considered 75523 SNPs mapped to putative promoter or enhancer regions. In anticipation that power to detect higher order epistasis would be low using an exhaustive search and a Bonferroni-corrected threshold for genome-wide significance (e.g., P?

SUBMITTER: Im C

PROVIDER: S-EPMC5839052 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Genome-wide search for higher order epistasis as modifiers of treatment effects on bone mineral density in childhood cancer survivors.

Im Cindy C Ness Kirsten K KK Kaste Sue C SC Chemaitilly Wassim W Moon Wonjong W Sapkota Yadav Y Brooke Russell J RJ Hudson Melissa M MM Robison Leslie L LL Yasui Yutaka Y Wilson Carmen L CL

European journal of human genetics : EJHG 20180118 2

Single-nucleotide polymorphisms (SNPs) contributing to interactions between regulatory elements that modulate gene transcription may explain some of the uncharacterized variation for complex traits. We explored this hypothesis among 856 adult survivors of pediatric cancer exposed to curative treatments that adversely affect bone mineral density (BMD). To restrict our search to interactions among SNPs in regulatory elements, our analysis considered 75523 SNPs mapped to putative promoter or enhanc ...[more]

PMID: 29348692

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Genome-wide search for higher order epistasis as modifiers of treatment effects on bone mineral density in childhood cancer survivors

Project description:Survivors of pediatric acute lymphoblastic leukemia (ALL) exposed to curative treatments that adversely affect BMD (age- and sex-adjusted BMD Z-scores, measured via QCT). Specifically, after SNP QC and annotation, we considered 75523 autosomal SNPs mapped to putative promoter or enhancer regions to restrict our search to 3-way SNP interactions that potentially reflect gene regulation events that influence BMD. We replicated 3-SNP interactions as modifiers of treatment effects in a cohort of adult survivors of non-ALL pediatric cancers (N=1428).

| EGAS00001002645 | EGA

Fast and accurate exhaustive higher-order epistasis search with BitEpi.

Project description:Complex genetic diseases may be modulated by a large number of epistatic interactions affecting a polygenic phenotype. Identifying these interactions is difficult due to computational complexity, especially in the case of higher-order interactions where more than two genomic variants are involved. In this paper, we present BitEpi, a fast and accurate method to test all possible combinations of up to four bi-allelic variants (i.e. Single Nucleotide Variant or SNV for short). BitEpi introduces a novel bitwise algorithm that is 1.7 and 56 times faster for 3-SNV and 4-SNV search, than established software. The novel entropy statistic used in BitEpi is 44% more accurate to identify interactive SNVs, incorporating a p-value-based significance testing. We demonstrate BitEpi on real world data of 4900 samples and 87,000 SNPs. We also present EpiExplorer to visualize the potentially large number of individual and interacting SNVs in an interactive Cytoscape graph. EpiExplorer uses various visual elements to facilitate the discovery of true biological events in a complex polygenic environment.

| S-EPMC8342486 | biostudies-literature

Anthropometric models of bone mineral content and areal bone mineral density based on the bone mineral density in childhood study.

Project description:UNLABELLED:New models describing anthropometrically adjusted normal values of bone mineral density and content in children have been created for the various measurement sites. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters. INTRODUCTION:Previous descriptions of children's bone mineral measurements by age have focused on segmenting diverse populations by race and sex without adjusting for anthropometric variables or have included the effects of a single anthropometric variable. METHODS:We applied multivariate semi-metric smoothing to the various pediatric bone-measurement sites using data from the Bone Mineral Density in Childhood Study to evaluate which of sex, race, age, height, weight, percent body fat, and sexual maturity explain variations in the population's bone mineral values. By balancing high adjusted R(2) values with clinical needs, two models are examined. RESULTS:At the spine, whole body, whole body sub head, total hip, hip neck, and forearm sites, models were created using sex, race, age, height, and weight as well as an additional set of models containing these anthropometric variables and percent body fat. For bone mineral density, weight is more important than percent body fat, which is more important than height. For bone mineral content, the order varied by site with body fat being the weakest component. Including more anthropometrics in the model reduces the overlap of the critical groups, identified as those individuals with a Z-score below -2, from the standard sex, race, and age model. CONCLUSIONS:If body fat is not available, the simpler model including height and weight should be used. The inclusion of multiple explanatory variables in the models provides the opportunity to calculate Z-scores that are adjusted with respect to the relevant anthropometric parameters.

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Low bone mineral density is associated with hypogonadism and cranial irradiation in male childhood cancer survivors.

Project description:We investigated if bone mineral density was related to testosterone deficiency and/or previous cancer treatment in men who were childhood cancer survivors. Men with untreated testosterone deficiency or previous treatment with cranial irradiation were at increased risk of impaired bone health. Prevention of osteoporosis should be considered in their follow-up. INTRODUCTION:Childhood cancer survivors (CCS) are at increased risk of hypogonadism. Reduced bone mineral density (BMD) has been reported in CCS but it is unclear whether this is due to hypogonadism or a direct effect of cancer therapy. This study investigated BMD in CCS, and association with hypogonadism, previous treatment and cancer type. METHODS:Investigation of 125 CCS (median age 33.7 at inclusion; 9.6 at diagnosis) and 125 age-matched population controls. Serum testosterone and luteinizing hormone were assayed and BMD at total hip and lumbar spine L1-L4 measured. The mean difference in BMD (g/cm2; 95% CI) between CCS and controls was analysed. Odds ratios (OR; 95% CI) for low BMD were also calculated. RESULTS:Overall, BMD in the CCS cohort did not significantly differ from controls. However, compared with eugonadal CCS, the CCS with untreated hypogonadism had lower BMD at the hip (mean difference -?0.139 (-?0.210; -?0.067); p?<?0.001) and spine (-?0.102 (-?0.174; -?0.030); p?=?0.006). They also had a higher risk of low hip BMD (OR 4.1 (1.3; 14); p?=?0.018). CCS treated with cranial irradiation also had lower BMD (hip -?0.076 (-?0.133; -?0.019); p?=?0.009; spine -?0.071 (-?0.124; -?0.018); p?=?0.009) compared with controls. The latter associations remained statistically significant after adjustment for hypogonadism. CONCLUSIONS:CCS with hypogonadism or previously treated with cranial irradiation are at increased risk of impaired bone health. Prevention of osteoporosis should be considered as an important part in future follow-up of these men.

| S-EPMC7280350 | biostudies-literature

Lumbar Spine Bone Mineral Apparent Density in Children: Results From the Bone Mineral Density in Childhood Study.

Project description:CONTEXT:Dual-energy X-ray absorptiometry (DXA) is a cornerstone of pediatric bone health assessment, yet differences in height-for-age confound the interpretation of areal bone mineral density (aBMD) measures. To reduce the confounding of short stature on spine bone density, use of bone mineral apparent density (BMAD) and height-for-age Z-score (HAZ)?adjusted aBMD (aBMDHAZ) are recommended. However, spine BMAD reference data are sparse, and the degree to which BMAD and aBMDHAZ account for height-related artifacts in bone density remains unclear. OBJECTIVE:We developed age-, sex-, and population ancestry?specific spine BMAD reference ranges; compared height-adjustment methods in accounting for shorter stature; and assessed the stability of these measures over time. DESIGN:Secondary analysis of data from a previous longitudinal study. PARTICIPANTS:Children and adolescents aged 5 to 19 years at baseline (n = 2014; 922 males; 22% black) from the Bone Mineral Density in Childhood Study. MAIN OUTCOME MEASURES:Lumbar spine BMAD and aBMDHAZ from DXA. RESULTS:Spine BMAD increased nonlinearly with age and was greater in blacks and females (all P < 0.001). Age-specific spine BMAD z-score reference curves were constructed for black and non?black males and females. Overall, both BMAD and aBMDHAZz scores reduced the confounding influence of shorter stature, but neither was consistently unbiased across all age ranges. Both BMAD and aBMDHAZz scores tracked strongly over 6 years (r = 0.70 to 0.80; all P < 0.001). CONCLUSION:This study provided robust spine BMAD reference ranges and demonstrated that BMAD and aBMDHAZ partially reduced the confounding influence of shorter stature on bone density.

| S-EPMC6397436 | biostudies-literature

Body composition and bone mineral density in childhood.

Project description:BACKGROUND:Body mass compartments may have different directions of influence on bone accrual. Studies of children are limited by relatively small sample sizes and typically make strong assumptions of linear regression. OBJECTIVE:To evaluate associations of overall body mass, components of overall body mass (fat-free and total fat), and components of total fat mass (truncal and non-truncal fat), measured via dual-energy X-ray absorptiometry (DXA) and anthropometry, with total body less head areal bone mineral density (aBMD) Z-score in mid-childhood. METHODS:We performed a cross-sectional study among 876 Boston-area children who had DXA measures. We evaluated linearity of associations using generalized additive models. RESULTS:Children were median 7.7 (range 6-10) years of age, and 61% were white. After adjustment for sociodemographics and other compartments of body mass, overall body mass, particularly the fat-free mass component, appeared to have a positive relationship with aBMD Z-score [e.g., 0.25 (95% CI: 0.23, 0.28) per 1-kg fat-free mass]. The relationship between truncal fat and aBMD Z-score appeared non-linear, with a negative association only in children with levels of fat mass in the upper 15th percentile [-0.17 (95% CI: -0.26, -0.07) aBMD Z-score per 1-kg truncal fat mass], while non-truncal fat mass was not associated with aBMD Z-score. CONCLUSIONS:Our analyses suggest that central adiposity is associated with lower aBMD Z-score only in children with the highest levels of abdominal fat. This finding raises the possibility of a threshold above which central adipose tissue becomes more metabolically active and thereby adversely impacts bone.

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Higher-order epistasis and phenotypic prediction.

Project description:Contemporary high-throughput mutagenesis experiments are providing an increasingly detailed view of the complex patterns of genetic interaction that occur between multiple mutations within a single protein or regulatory element. By simultaneously measuring the effects of thousands of combinations of mutations, these experiments have revealed that the genotype-phenotype relationship typically reflects not only genetic interactions between pairs of sites but also higher-order interactions among larger numbers of sites. However, modeling and understanding these higher-order interactions remains challenging. Here we present a method for reconstructing sequence-to-function mappings from partially observed data that can accommodate all orders of genetic interaction. The main idea is to make predictions for unobserved genotypes that match the type and extent of epistasis found in the observed data. This information on the type and extent of epistasis can be extracted by considering how phenotypic correlations change as a function of mutational distance, which is equivalent to estimating the fraction of phenotypic variance due to each order of genetic interaction (additive, pairwise, three-way, etc.). Using these estimated variance components, we then define an empirical Bayes prior that in expectation matches the observed pattern of epistasis and reconstruct the genotype-phenotype mapping by conducting Gaussian process regression under this prior. To demonstrate the power of this approach, we present an application to the antibody-binding domain GB1 and also provide a detailed exploration of a dataset consisting of high-throughput measurements for the splicing efficiency of human pre-mRNA [Formula: see text] splice sites, for which we also validate our model predictions via additional low-throughput experiments.

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Association of Insulin-like Growth Factor-1 with Bone Mineral Density in Survivors of Childhood Acute Leukemia.

Project description:In this study, we investigated bone mineral deficits in children who survived childhood acute leukemia and explored the association between the insulin-like growth factor-1 (IGF-1) level and bone mineral density (BMD). This retrospective analysis enrolled 214 patients treated for acute leukemia, measuring various factors including height, weight, body mass index (BMI), and lumbar spine BMD after the end of treatment. The study found an overall prevalence of low BMD in 15% of participants. Notably, IGF-1 levels were significantly different between patients with low BMD and those with normal BMD, and correlation analyses revealed associations of the IGF-1 level and BMI with lumbar spine BMD. Regression analyses further supported this relationship, suggesting that higher IGF-1 levels were associated with a decreased risk of low BMD. The study findings suggest that IGF-1 may serve as a valuable tool for evaluating and predicting osteoporosis in survivors of childhood acute leukemia.

| S-EPMC11011034 | biostudies-literature

Relevance of Higher-Order Epistasis in Drug Resistance.

Project description:We studied five chemically distinct but related 1,3,5-triazine antifolates with regard to their effects on growth of a set of mutants in dihydrofolate reductase. The mutants comprise a combinatorially complete data set of all 16 possible combinations of four amino acid replacements associated with resistance to pyrimethamine in the malaria parasite Plasmodium falciparum. Pyrimethamine was a mainstay medication for malaria for many years, and it is still in use in intermittent treatment during pregnancy or as a partner drug in artemisinin combination therapy. Our goal was to investigate the extent to which the alleles yield similar adaptive topographies and patterns of epistasis across chemically related drugs. We find that the adaptive topographies are indeed similar with the same or closely related alleles being fixed in computer simulations of stepwise evolution. For all but one of the drugs the topography features at least one suboptimal fitness peak. Our data are consistent with earlier results indicating that third order and higher epistatic interactions appear to contribute only modestly to the overall adaptive topography, and they are largely conserved. In regard to drug development, our data suggest that higher-order interactions are likely to be of little value as an advisory tool in the choice of lead compounds.

| S-EPMC7782864 | biostudies-literature

Pediatric Reference Ranges for Ultradistal Radius Bone Density: Results from the Bone Mineral Density in Childhood Study.

Project description:The ultradistal (UD) radius is rich in trabecular bone and is easily measured by dual energy X-ray absorptiometry (DXA). UD radius areal bone mineral density (aBMD) may help identify trabecular bone deficits, but reference data are needed for research and clinical interpretation of this measure. We developed age-, sex-, and population ancestry-specific reference ranges for UD radius aBMD assessed by DXA and calculated Z-scores. We examined tracking of UD radius aBMD Z-scores over 6 years and determined associations between UD radius aBMD Z-scores and other bone measures by DXA and peripheral quantitative computed tomography. Multicenter longitudinal study. A total of 2014 (922 males, 22% African American) children ages 5 to 19 years at enrollment who participated in the Bone Mineral Density in Childhood Study. UD radius aBMD. UD radius aBMD increased nonlinearly with age (P < 0.001) and tended to be greater in males versus females (P = 0.054). Age-, sex-, and ancestry-specific UD radius aBMD reference curves were constructed. UD radius aBMD Z-scores positively associated with Z-scores at other skeletal sites (r = 0.54-0.64, all P < 0.001) and peripheral quantitative computed tomography measures of distal radius total volumetric BMD (r = 0.68, P < 0.001) and trabecular volumetric BMD (r = 0.70, P < 0.001), and was weakly associated with height Z-score (r = 0.09, P = 0.015). UD radius aBMD Z-scores tracked strongly over 6 years, regardless of pubertal stage (r = 0.66-0.69; all P < 0.05). UD radius aBMD Z-scores strongly associated with distal radius trabecular bone density, with marginal confounding by stature. These reference data may provide a valuable resource for bone health assessment in children.

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