Seven days of ischemic preconditioning augments hypoxic exercise ventilation and muscle oxygenation in recreationally trained males.

This investigation sought to assess whether single or repeated bouts of ischemic preconditioning (IPC) could improve oxyhemoglobin saturation ([Formula: see text]) and/or attenuate reductions in muscle tissue saturation index (TSI) during submaximal hypoxic exercise. Fifteen healthy young men completed submaximal graded exercise under four experimental conditions: 1) normoxia (NORM), 2) hypoxia (HYP) [oxygen fraction of inspired air ([Formula: see text]) = 0.14, ∼3,200 m], 3) hypoxia preceded by a single session of IPC (IPC1-HYP), and 4) hypoxia preceded by seven sessions of IPC, one a day for 7 consecutive days (IPC7-HYP). IPC7-HYP heightened minute ventilation (V̇e) at 80% HYP peak cycling power output (Wpeak) (+10.47 ± 3.35 L·min-1, P = 0.006), compared with HYP, as a function of increased breathing frequency. Both IPC1-HYP (+0.17 ± 0.04 L·min-1, P < 0.001) and IPC7-HYP (+0.16 ± 0.04 L·min-1, P < 0.001) elicited greater oxygen consumption (V̇o2) across exercise intensities compared with NORM, whereas V̇o2 was unchanged with HYP alone. [Formula: see text] was unchanged by either IPC condition at any exercise intensity, yet the reduction of muscle TSI during resting hypoxic exposure was attenuated by IPC7-HYP (+9.9 ± 3.6%, P = 0.040) compared with HYP, likely as a function of reduced local oxygen extraction. Considering all exercise intensities, IPC7-HYP attenuated reductions of TSI with HYP (+6.4 ± 1.8%, P = 0.001). Seven days of IPC heightens ventilation, posing a threat to ventilatory efficiency, during high-intensity submaximal hypoxic exercise and attenuates reductions in hypoxic resting and exercise muscle oxygenation in healthy young men. A single session of IPC may be capable of modulating hypoxic ventilation; however, our present population was unable to demonstrate this with certainty.

Substrate metabolism during recovery from circuit resistance exercise in persons with spinal cord injury.

INTRODUCTION: Whole body energy expenditure and lipid oxidation (Lox) are upregulated during and after exercise. Persons with spinal cord injury (SCI) generally have a blunted ability to utilize fat during exercise, but it is unknown if their substrate partitioning is affected during recovery from exercise. PURPOSE: To determine the effect of a single session of upper body circuit resistance exercise (CRE) on energy expenditure and Lox during exercise recovery in persons with and without SCI. METHODS: Twenty four persons (3 groups; 7 male and 1 female per group) without paralysis (neurologically intact; N) or with chronic (≥ 1 yr) paraplegia (P) or tetraplegia (T) participated. Energy expenditure and substrate partitioning were assessed via indirect calorimetry before, during, and three times after (up to 120 min after) a single session of CRE, or time-matched seated control (CON). RESULTS: During CRE, all groups experienced a similar relative increase in oxygen consumption (49 ± 13, 55 ± 11, and 48 ± 15% VO2peak for N, P, and T, respectively). The Post0-120 energy expenditure was greater following CRE vs. CON (P < 0.01) and independent of injury characteristics (10.6, 22.6, and 14.3% higher than CON for N, P, and T; P = 0.21). The absolute increase in Lox above CON during recovery was similar for N, P, and T (5.74 ± 2.81, 6.62 ± 3.10, and 4.50 ± 3.91 g, respectively; P = 0.45). CONCLUSIONS: Energy expenditure and lipid utilization was increased similarly following circuit exercise in persons without and with spinal cord injury in a manner independent of level of injury.

Physiological responses to moderate intensity continuous and high-intensity interval exercise in persons with paraplegia.

STUDY DESIGN: Randomized crossover. OBJECTIVES: To test differences in the duration and magnitude of physiological response to isocaloric moderate intensity continuous (MICE) and high-intensity interval exercise (HIIE) sessions in persons with spinal cord injury (SCI). SETTING: Academic medical center in Miami, FL, USA. METHODS: Ten adult men (mean ± s.d.; 39 ± 10 year old) with chronic (13.2 ± 8.8 year) paraplegia (T2-T10) completed a graded exercise test. Then, in a randomized order, participants completed MICE and HIIE for a cost of 120 kcal. MICE was performed at 24.6% POpeak. During HIIE, exercise was completed in 2 min work and recovery phases at 70%:10% POpeak. RESULTS: MICE and HIIE were isocaloric (115.9 ± 21.8 and 116.6 ± 35.0 kcal, respectively; p = 0.903), but differed in duration (39.8 ± 4.6 vs 32.2 ± 6.2 min; p < 0.001) and average respiratory exchange ratio (RER; 0.90 ± 0.08 vs 1.01 ± 0.07; p = 0.002). During MICE, a workrate of 24.6 ± 6.7% POpeak elicited a V̇O2 of 53.1 ± 6.5% V̇O2peak (10.1 ± 2.2 ml kg-1 min-1). During HIIE, a workrate at 70% POpeak elicited 88.3 ± 6.7% V̇O2peak (16.9 ± 4.2 ml kg-1 min-1), and 29.4 ± 7.7% of the session was spent at or above 80% V̇O2peak. During HIIE working phase, RER declined from the first to last interval (1.08 ± 0.07 vs 0.98 ± 0.09; p < 0.001), reflecting an initially high but declining glycolytic rate. CONCLUSIONS: Compared with MICE, HIIE imposed a greater physiological stimulus while requiring less time to achieve a target caloric expenditure. Thus, exercise intensity might be an important consideration in the tailoring of exercise prescription to address the cardiometabolic comorbidities of SCI.

hgvs: A Python package for manipulating sequence variants using HGVS nomenclature: 2018 Update.

The Human Genome Variation Society (HGVS) nomenclature guidelines encourage the accurate and standard description of DNA, RNA, and protein sequence variants in public variant databases and the scientific literature. Inconsistent application of the HGVS guidelines can lead to misinterpretation of variants in clinical settings. Reliable software tools are essential to ensure consistent application of the HGVS guidelines when reporting and interpreting variants. We present the hgvs Python package, a comprehensive tool for manipulating sequence variants according to the HGVS nomenclature guidelines. Distinguishing features of the hgvs package include: (1) parsing, formatting, validating, and normalizing variants on genome, transcript, and protein sequences; (2) projecting variants between aligned sequences, including those with gapped alignments; (3) flexible installation using remote or local data (fully local installations eliminate network dependencies); (4) extensive automated tests; and (5) open source development by a community from eight organizations worldwide. This report summarizes recent and significant updates to the hgvs package since its original release in 2014, and presents results of extensive validation using clinical relevant variants from ClinVar and HGMD.

Characterization of large structural genetic mosaicism in human autosomes.

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

FTO genotype is associated with phenotypic variability of body mass index.

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Sheath flow SERS for chemical profiling in urine.

The molecular specificity and sensitivity of surface enhanced Raman scattering (SERS) makes it an attractive method for biomedical diagnostics. Here we present results demonstrating the utility and complications for SERS characterization in urine. The chemical fingerprint characteristics of Raman spectra suggest its use as a label free diagnostic; however, the complex composition of biological fluids presents a tremendous challenge. In particular, the limited number of surface sites and competing absorption tend to mask the presence of analytes in solution, particularly when the solution contains multiple analytes. To address these problems and characterize biological fluids we have demonstrated a sheath-flow interface for SERS detection. This sheath-flow SERS interface uses hydrodynamic focusing to confine analyte molecules eluting out of a column onto a planar SERS substrate where the molecules are detected by their intrinsic SERS signal. In this report we compare the direct detection of benzoylecgonine in urine using DSERS with chemical profiling by capillary zone electrophoresis and sheath-flow SERS detection. The SERS spectrum from the observed migration peaks can identify benzoylecgonine and other distinct spectra are also observed, suggesting improved chemical diagnostics in urine. With over 2000 reported compounds in urine, identification of each of the detected species is an enormous task. Nonetheless, these samples provide a benchmark to establish the potential clinical utility of sheath-flow SERS detection.

The Effect of a Community-Based Exercise Program on Inflammation, Metabolic Risk, and Fitness Levels Among Persons Living with HIV/AIDS.

The human immunodeficiency virus (HIV) pandemic remains a top national health priority. Chronic inflammation may be a critical component in the disease course of HIV as C-reactive protein (CRP) is elevated and associated with increased mortality. This study examined the effect of 3 months of combined aerobic and resistance exercise training among a diverse cohort of HIV-infected men and women. The fixed effect of time for CRP was found to be non-significant (F[1,57.3] = 1.7, p = 0.19). There was a significant fixed effect for time for upper body (F[1,51.6] = 18.1, p < 0.05) and lower body strength (F[1,48.0] = 15.7, p < 0.05) and significant declines in diastolic blood pressure (p = 0.002) and waist circumference (p = 0.027). Though levels of CRP were not impacted after 3 months training, participants demonstrated a significant increase in muscular strength as well as beneficial changes in metabolic risk factors. Future studies should focus on determining the optimal exercise intervention length and mode to reduce inflammation among individuals living with HIV.

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

Genome-wide association study of prostate cancer identifies a second risk locus at 8q24.

Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.

Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course.

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻8) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹7), MC4R (P = 4.41 × 10⁻¹7), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻9), GNPDA2 (P = 1.11 × 10⁻8) and POMC (P = 4.94 × 10⁻8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.

A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits.

Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta-analysis or pooled analysis, however, might not be suitable for such analysis because individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. We propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. We present two illustrative applications, one for a meta-analysis of separate case-control studies of six distinct cancers and another for pooled analysis of a case-control study of glioma, a class of brain tumors that contains heterogeneous subtypes. Both the applications and additional simulation studies demonstrate that the proposed methods offer improved power and more interpretable results when compared to traditional methods for the analysis of heterogeneous traits. The proposed framework has applications beyond genetic association studies.

Increased SERS detection efficiency for characterizing rare events in flow.

Improved surface-enhanced Raman scattering (SERS) measurements of a flowing aqueous sample are accomplished by combining line focus optics with sheath-flow SERS detection. The straightforward introduction of a cylindrical lens into the optical path of the Raman excitation laser increases the efficiency of SERS detection and the reproducibility of SERS signals at low concentrations. The width of the line focus is matched to the width of the sample capillary from which the analyte elutes under hydrodynamic focusing conditions, allowing for increased collection across the SERS substrate while maintaining the power density below the damage threshold at any specific point. We show that a 4× increase in power spread across the line increases the signal-to-noise ratio by a factor of 2 for a variety of analytes, such as rhodamine 6G, amino acids, and lipid vesicles, without any detectable photodamage. COMSOL simulations and Raman maps elucidate the hydrodynamic focusing properties of the flow cell, providing a clearer picture of the confinement effects at the surface where the sample exits the capillary. The lipid vesicle results suggest that the combination of hydrodynamic focusing and increased optical collection enables the reproducible detection of rare events, in this case individual lipid vesicles.

Kinetic trapping of metastable amino acid polymorphs.

Second harmonic generation (SHG) microscopy measurements indicate that inkjet-printed racemic solutions of amino acids can produce nanocrystals trapped in metastable polymorph forms upon rapid solvent evaporation. Polymorphism impacts the composition, distribution, and physico-kinetic properties of organic solids, with energetic arguments favoring the most stable polymorph. In this study, unfavored noncentrosymmetric crystal forms were observed by SHG microscopy. Polarization-dependent SHG measurement and synchrotron X-ray microdiffraction analysis of individual printed drops are consistent with formation of homochiral crystal production. Fundamentally, these results provide evidence supporting the ubiquity of Ostwald's Rule of Stages, describing the hypothesized transitioning of crystals between metastable polymorphic forms in the early stages of crystal formation. Practically, the presence of homochiral metastable forms has implications on chiral resolution and on solid form preparations relying on rapid solvent evaporation.

Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies.

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23.

Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption.

We report the first genome-wide association study of habitual caffeine intake. We included 47,341 individuals of European descent based on five population-based studies within the United States. In a meta-analysis adjusted for age, sex, smoking, and eigenvectors of population variation, two loci achieved genome-wide significance: 7p21 (P = 2.4 × 10(-19)), near AHR, and 15q24 (P = 5.2 × 10(-14)), between CYP1A1 and CYP1A2. Both the AHR and CYP1A2 genes are biologically plausible candidates as CYP1A2 metabolizes caffeine and AHR regulates CYP1A2.

A two-platform design for next generation genome-wide association studies.

Genome-wide association studies (GWAS) have been successful in their search for common genetic variants associated with complex traits and diseases. With new advances in array technologies together with available genetic reference sets, the next generation of GWAS will extend the search for associations with uncommon SNPs (1% ≤ MAF ≤ 10%). Two possible approaches are genotyping all participants, a prohibitively expensive option for large GWAS, or using a combination of genotyping and imputation. Here, we consider a two platform method that genotypes all participants on a standard genotyping array, designed to identify common variants, and then supplements that data by genotyping only a small proportion of the participants on a platform that has higher coverage for uncommon SNPs. This subset of the study population is then included as part of the imputation reference set. To demonstrate the use of this two-platform design, we evaluate its potential efficiency using a newly available dataset containing 756 individuals genotyped on both the Illumina Human OmniExpress and Omni2.5 Quad. Although genotyping all individuals on the denser array would be ideal, we find that genotyping only 100 individuals on this array, in combination with imputation, leads to only a modest loss of power for detecting associations. However, the loss of power due to imputation can be more substantial if the relative risks for rare variants are significantly larger than those previously observed for common variants.