Arterial oxygen desaturation during moderate hypoxia hinders sensorimotor performance.

INTRODUCTION: Moderate hypoxia may impact cognitive and sensorimotor performance prior to self-recognized impairments. Therefore, rapid and objective assessment tools to identify people at risk of impaired function during moderate hypoxia is needed. PURPOSE: Test the hypothesis that reductions in arterial oxygen saturation during moderate normobaric hypoxia (FiO2 = 14%) decreases gamified sensorimotor performance as measured by alterations of motor acuity. METHODS: Following three consecutive days of practice, thirty healthy adults (25 ± 5 y, 10 females) completed three bouts of the tablet-based gamified assessment (Statespace Labs, Inc.) of motor acuity at Baseline and 60 and 90 min after exposure to 13.8 ± 0.2% (hypoxia) and 20.1 ± 0.4% (normoxia) oxygen. The gamified assessment involved moving the tablet to aim and shoot at targets. Both conditions were completed on the same day and were administered in a single-blind, block randomized manner. Performance metrics included shot time and shot variability. Arterial oxyhemoglobin saturation estimated via forehead pulse oximetry (SpO2). Data were analyzed using linear mixed effects models. RESULTS: Compared to normoxia (99±1%), SpO2 was lower (p<0.001) at 60 (89±3%) and 90 (90±2%) min of hypoxia. Shot time was unaffected by decreases in SpO2 (0.012, p = 0.19). Nor was shot time affected by the interaction between SpO2 decrease and baseline performance (0.006, p = 0.46). Shot variability was greater (i.e., less precision, worse performance) with decreases in SpO2 (0.023, p = 0.02) and depended on the interaction between SpO2 decrease and baseline performance (0.029, p< 0.01). CONCLUSION: Decreases in SpO2 during moderate hypoxic exposure hinders sensorimotor performance via decreased motor acuity, i.e., greater variability (less precision) with no change in speed with differing decreases in SpO2. Thus, personnel who are exposed to moderate hypoxia and have greater decreases in SpO2 exhibit lower motor acuity, i.e., less precise movements even though decision time and movement speed are unaffected.

Gamified assessment of cognitive performance during moderate hypoxia.

INTRODUCTION: There is a need for rapid and objective assessment tools to identify people at risk of impaired cognitive function during hypoxia. PURPOSE: To test the hypotheses that performance on gamified cognitive tests examining the cognitive domains of executive function (Gridshot), working memory (Capacity) and spatial tracking (Multitracker) will be reduced during normobaric exposure to moderate normobaric hypoxia. METHODS: Following three consecutive days of practice, twenty-one healthy adults (27 ± 5 y, 9 females) completed five 1-min rounds of the tablet-based games Gridshot, Capacity, and Multitracker (Statespace Labs, Inc.) at Baseline and 60 and 90 min after exposure to 14.0 ± 0.2% (hypoxia) and 20.6 ± 0.3% (normoxia) oxygen. Both conditions were completed on the same day and were administered in a single-blind, block randomized manner. Arterial oxyhemoglobin saturation was estimated via forehead pulse oximetry (SpO2). Data were analyzed using ANCOVA with a covariate of Baseline. RESULTS: Compared to normoxia (98 ± 1%), SpO2 was lower (p < 0.001) at 60 (91 ± 3%) and 90 (91 ± 2%) min of hypoxia. No condition x time interaction effects were identified for any gamified cognitive tests (p ≥ 0.32). A main effect of condition was identified for Capacity (p = 0.05) and Multitracker (p = 0.04), but not Gridshot (p = 0.33). Post hoc analyses of the composite scores for both Capacity (p = 0.11) and Multitracker (p = 0.73) demonstrated no difference between conditions. CONCLUSION: Performance on gamified cognitive tests was not consistently affected by acute normobaric moderate hypoxic exposure.

Assessment of human expertise and movement kinematics in first-person shooter games.

In contrast to traditional professional sports, there are few standardized metrics in professional esports (competitive multiplayer video games) for assessing a player's skill and ability. We assessed the performance of professional-level players in Aim LabTM, a first-person shooter training and assessment game, with two target-shooting tasks. These tasks differed primarily in target size: the task with large targets provided an incentive to be fast but imprecise and the task with large targets provided an incentive to be precise but slow. Each player's motor acuity was measured by characterizing the speed-accuracy trade-off in shot behavior: shot time (elapsed time for a player to shoot at a target) and shot spatial error (distance from center of a target). We also characterized the fine-grained kinematics of players' mouse movements. Our findings demonstrate that: 1) movement kinematics depended on task demands; 2) individual differences in motor acuity were significantly correlated with kinematics; and 3) performance, combined across the two target sizes, was poorly characterized by Fitts Law. Our approach to measuring motor acuity has widespread applications not only in esports assessment and training, but also in basic (motor psychophysics) and clinical (gamified rehabilitation) research.

Long-Term Motor Learning in the "Wild" With High Volume Video Game Data.

Motor learning occurs over long periods of practice during which motor acuity, the ability to execute actions more accurately, precisely, and in less time, improves. Laboratory-based studies of motor learning are typically limited to a small number of participants and a time frame of minutes to several hours per participant. There is a need to assess the generalizability of theories and findings from lab-based motor learning studies on larger samples and time scales. In addition, laboratory-based studies of motor learning use relatively simple motor tasks which participants are unlikely to be intrinsically motivated to learn, limiting the interpretation of their findings in more ecologically valid settings ("in the wild"). We studied the acquisition and longitudinal refinement of a complex sensorimotor skill embodied in a first-person shooter video game scenario, with a large sample size (N = 7174, 682,564 repeats of the 60 s game) over a period of months. Participants voluntarily practiced the gaming scenario for up to several hours per day up to 100 days. We found improvement in performance accuracy (quantified as hit rate) was modest over time but motor acuity (quantified as hits per second) improved considerably, with 40-60% retention from 1 day to the next. We observed steady improvements in motor acuity across multiple days of video game practice, unlike most motor learning tasks studied in the lab that hit a performance ceiling rather quickly. Learning rate was a non-linear function of baseline performance level, amount of daily practice, and to a lesser extent, number of days between practice sessions. In addition, we found that the benefit of additional practice on any given day was non-monotonic; the greatest improvements in motor acuity were evident with about an hour of practice and 90% of the learning benefit was achieved by practicing 30 min per day. Taken together, these results provide a proof-of-concept in studying motor skill acquisition outside the confines of the traditional laboratory, in the presence of unmeasured confounds, and provide new insights into how a complex motor skill is acquired in an ecologically valid setting and refined across much longer time scales than typically explored.

Biases and errors on allele frequency estimation and disease association tests of next-generation sequencing of pooled samples.

Next-generation sequencing is widely used to study complex diseases because of its ability to identify both common and rare variants without prior single nucleotide polymorphism (SNP) information. Pooled sequencing of implicated target regions can lower costs and allow more samples to be analyzed, thus improving statistical power for disease-associated variant detection. Several methods for disease association tests of pooled data and for optimal pooling designs have been developed under certain assumptions of the pooling process, for example, equal/unequal contributions to the pool, sequencing depth variation, and error rate. However, these simplified assumptions may not portray the many factors affecting pooled sequencing data quality, such as PCR amplification during target capture and sequencing, reference allele preferential bias, and others. As a result, the properties of the observed data may differ substantially from those expected under the simplified assumptions. Here, we use real datasets from targeted sequencing of pooled samples, together with microarray SNP genotypes of the same subjects, to identify and quantify factors (biases and errors) affecting the observed sequencing data. Through simulations, we find that these factors have a significant impact on the accuracy of allele frequency estimation and the power of association tests. Furthermore, we develop a workflow protocol to incorporate these factors in data analysis to reduce the potential biases and errors in pooled sequencing data and to gain better estimation of allele frequencies. The workflow, Psafe, is available at http://bioinformatics.med.yale.edu/group/.

Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations.

Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine.

Variation in NGFB is associated with primary affective disorders in women.

Affective disorders (AFDs) are highly comorbid with substance dependence (SD) and both are genetically influenced. However, the specific etiology of the comorbidity is not well understood. We genotyped an array of 1,350 single nucleotide polymorphisms (SNPs) in or near 130 genes in 868 European-Americans (EAs), including 182 individuals with primary AFDs (PAFDs), 214 with SD comorbid with AFD (CAFD), and 472 screened controls. NGFB, which encodes nerve growth factor ß and was represented in the array by 15 SNPs, showed the strongest evidence of association, but only among women with PAFDs. Six of the SNPs showed nominally significant association with PAFDs in women (P's = 0.0007-0.01); three (rs2856813, rs4332358, and rs10776799) were empirically significant based on 1,000,000 permutations (P's = 0.008-0.015). Seven haplotypes were significantly associated with PAFDs in women (P's = 0.0014-0.01), of which six were significant based on empirical permutation analysis (minimal P = 0.0045). Four diplotypes were significantly associated with PAFDs in women (global P's = 0.001-0.01). The specific diplotype GG-TC, reconstructed from rs2856813 and rs6678788, showed the strongest evidence of association with PAFDs in women (OR = 4.07, P = 4.2E-05). No SNPs or haplotypes were associated with PAFDs in men or with CAFDs in either sex. We conclude that variation in NGFB is a risk factor for PAFDs in women, but not for CAFD.

Identification of population substructure among Jews using STR markers and dependence on reference populations included.

BACKGROUND: Detecting population substructure is a critical issue for association studies of health behaviors and other traits. Whether inherent in the population or an artifact of marker choice, determining aspects of a population's genetic history as potential sources of substructure can aid in design of future genetic studies. Jewish populations, among which association studies are often conducted, have a known history of migrations. As a necessary step in understanding population structure to conduct valid association studies of health behaviors among Israeli Jews, we investigated genetic signatures of this history and quantified substructure to facilitate future investigations of these phenotypes in this population. RESULTS: Using 32 autosomal STR markers and the program STRUCTURE, we differentiated between Ashkenazi (AJ, N = 135) and non-Ashkenazi (NAJ, N = 226) Jewish populations in the form of Northern and Southern geographic genetic components (AJ north 73%, south 23%, NAJ north 33%, south 60%). The ability to detect substructure within these closely related populations using a small STR panel was contingent on including additional samples representing major continental populations in the analyses. CONCLUSIONS: Although clustering programs such as STRUCTURE are designed to assign proportions of ancestry to individuals without reference population information, when Jewish samples were analyzed in the absence of proxy parental populations, substructure within Jews was not detected. Generally, for samples with a given grandparental country of birth, STRUCTURE assignment values to Northern, Southern, African and Asian clusters agreed with mitochondrial DNA and Y-chromosomal data from previous studies as well as historical records of migration and intermarriage.

Population admixture modulates risk for alcohol dependence.

The admixture of different ancestral populations in America may have important implications for the risk for psychiatric disorders, as it appears to have for other medical disorders. The present study investigated the role of population admixture in risk for several psychiatric disorders in European-Americans (EAs) and African-Americans (AAs). This is a multisite study with 3,792 subjects recruited from across the United States, including 3,119 EAs and 673 AAs. These subjects included healthy controls and those with substance dependence (SD) [including alcohol dependence (AD), cocaine dependence, and opioid dependence], social phobia, affective disorders, and schizophrenia. In addition, DNA was included from 78 West Africans. The degree of admixture for each subject was estimated by analysis of a set of ancestry-informative genetic markers using the program STRUCTURE, and was compared between cases and controls. As noted previously, the degree of admixture in AAs was higher than EAs. In EAs, the degree of admixture (with African ancestry) was significantly lower in patients with SD (mainly AD) than controls (P = 0.009 for SD; P = 0.008 for AD). This finding suggests that population admixture may modulate risk for alcohol dependence. Population admixture might protect against alcohol dependence by increasing average heterozygosity and reducing the risk of deleterious recessive alleles. We cannot exclude the possibility that the results might have been influenced by selection bias due to the multisite nature of the study.

Demographic changes and marker properties affect detection of human population differentiation.

BACKGROUND: Differentiating genetically between populations is valuable for admixture and population stratification detection and in understanding population history. This is easy to achieve for major continental populations, but not for closely related populations. It has been claimed that a large marker panel is necessary to reliably distinguish populations within a continent. We investigated whether empirical genetic differentiation could be accomplished efficiently among three Asian populations (Hmong, Thai, and Chinese) using a small set of highly variable markers (15 tetranucleotide and 17 dinucleotide repeats). RESULTS: Hmong could be differentiated from Thai and Chinese based on multi-locus genotypes, but Thai and Chinese were indistinguishable from each other. We found significant evidence for a recent population bottleneck followed by expansion in the Hmong that was not present in the Thai or Chinese. Tetranucleotide repeats were less useful than dinucleotide repeat markers in distinguishing between major continental populations (Asian, European, and African) while both successfully distinguished Hmong from Thai and Chinese. CONCLUSION: Demographic history contributes significantly to robust detection of intracontinental population structure. Populations having experienced a rapid size reduction may be reliably distinguished as a result of a genetic drift -driven redistribution of population allele frequencies. Tetranucleotide markers, which differ from dinucleotide markers in mutation mechanism and rate, are similar in information content to dinucleotide markers in this situation. These factors should be considered when identifying populations suitable for gene mapping studies and when interpreting interpopulation relationships based on microsatellite markers.