Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

A Plasma 5-Marker Host Biosignature Identifies Tuberculosis in High and Low Endemic Countries

Background: Several host inflammatory markers have been proposed as biomarkers for diagnosis and treatment response in Tuberculosis (TB), but few studies compare their utility in different demographic, ethnic, and TB endemic settings. Methods: Fifty-four host biomarkers were evaluated in plasma samples obtained from presumed TB cases recruited at the Oslo University Hospital in Norway, and a health center in Cape Town, South Africa. Based on clinical and laboratory assessments, participants were classified as having TB or other respiratory diseases (ORD). The concentrations of biomarkers were analyzed using the Luminex multiplex platform. Results: Out of 185 study participants from both study sites, 107 (58%) had TB, and 78 (42%) ORD. Multiple host markers showed diagnostic potential in both the Norwegian and South African cohorts, with I-309 as the most accurate single marker irrespective of geographical setting. Although study site-specific biosignatures had high accuracy for TB, a site-independent 5-marker biosignature (G-CSF, C3b/iC3b, procalcitonin, IP-10, PDGF-BB) was identified diagnosing TB with a sensitivity of 72.7% (95% CI, 49.8–82.3) and specificity of 90.5% (95% CI, 69.6–98.8) irrespective of geographical site. Conclusion: A 5-marker host plasma biosignature has diagnostic potential for TB disease irrespective of TB setting and should be further explored in larger cohorts

Relationship between hippocampal subfield volumes and memory function in adults born preterm with very low birth weight (VLBW)

Background: Being born preterm with very low birth weight (VLBW) is related to aberrant brain development. Hippocampus is a brain region particularly vulnerable to injury, for instance from consequences following preterm birth. The hippocampus is a complex structure with distinct subfields related to specific memory functions which are differently affected by neuropathological conditions. The relationship between deviations in hippocampal subfields and memory function has not been studied in adults born preterm with VLBW previously. Aims: In this long-term follow-up study of a geographically based cohort (birth years 1986-88) of VLBW individuals and term born controls with normal birth weight, the main aim was to examine group differences in memory function and hippocampal volumes at age 26 years. We also explored hippocampal structure-function relationships in the VLBW group. Methods: Fifty-two VLBW and 82 control individuals aged 26 years were examined clinically of whom 44 VLBW and 70 controls had high-quality structural cerebral MRI at 3T. The participants were assessed with subtests from Wechsler Memory Scale and Cambridge Neuropsychological Test Automated Battery on verbal, visual and working memory. From the T1 weighted 3D images, hippocampal subfield volumes were estimated in FreeSurfer 6.0. In addition to group comparisons, partial correlations were performed in the VLBW group between hippocampal subfields’ volumes and neonatal risk factors, and between reduced hippocampal subfields’ volumes and performance on the memory tests. Results: Adults with VLBW had lower verbal, visual and working memory scores compared with term born control adults. Absolute hippocampal total and most subfield volumes were smaller in the VLBW group than in the control group, but with different findings in men and women. When adjusting for intracranial volume, left and right cornu ammonis fields and left dentate gyrus were smaller in VLBW women, while the right subiculum was smaller in VLBW men compared with control women and men, respectively. There was a negative correlation between days on mechanical ventilation and volume of the left subiculum in the VLBW group. Smaller left dentate gyrus volume was associated with lower visual memory performance in the VLBW group. Conclusions: Adults born preterm with VLBW had lower performance on memory tests and smaller hippocampi compared with term born controls, and volume of dentate gyrus was associated with visual memory. Hippocampal subfield volumes seem to be differently affected following preterm birth in VLBW men and women

CCL1 and IL-2Ra differentiate Tuberculosis disease from latent infection Irrespective of HIV infection in low TB burden countries

Objectives: To evaluate the performance of selected host immunological biomarkers in differentiating tuberculosis (TB) disease from latent TB infection (LTBI) in HIV uninfected and infected individuals enrolled in TB low-burden countries. Design: Participants with TB disease (N = 85) and LTBI (N = 150) were recruited from prospective cohorts at hospitals in Norway and Denmark. Plasma concentrations of 54 host markers were assessed by Luminex multiplex immunoassays. Using receiver operator characteristic curves and general discriminant analysis, we determined the abilities of individual and combined biomarkers to discriminate between TB disease and LTBI including when patients were stratified according to HIV infection status. Results: Regardless of the groups compared, CCL1 and IL-2Ra were the most accurate single biomarkers in differentiating TB disease from LTBI. Regardless of HIV status, a 4-marker signature (CCL1+RANTES+CRP+MIP-1α) derived from a training set (n = 155) differentiated TB disease from LTBI in the test set (n = 67) with a sensitivity of 56.0% (95% CI, 34.9–75.6) and a specificity of 85.7% (95% CI, 71.5–94.6). A 5-marker signature derived from the HIV uninfected group (CCL1+RANTES+MIP-1α+procalcitonin+IP-10) performed in HIV-infected individuals with a sensitivity of 75.0% and a specificity of 96.7% after leave-one-out cross validation. A 2-marker signature (CCL1+TNF-α) identified in HIV-infected persons performed in HIV-uninfected with a sensitivity and specificity of 66.7% and 100% respectively in the test set. Conclusions: Plasma CCL1 and IL-2Ra have potential as biomarkers for differentiating TB disease from LTBI in low TB burden settings unaffected by HIV infection. Combinations between these and other biomarkers in bio-signatures for global use warrant further exploration

Relationship between hippocampal subfield volumes and memory function in adults born preterm with very low birth weight (VLBW)

Background:Being born preterm with very low birth weight (VLBW) is related to aberrant brain development. Hippocampus is a brain region particularly vulnerable to injury, for instance from consequences following preterm birth. The hippocampus is a complex structure with distinct subfields related to specific memory functions which are differently affected by neuropathological conditions. The relationship between deviations in hippocampal subfields and memory function has not been studied in adults born preterm with VLBW previously. Aims: In this long-term follow-up study of a geographically based cohort (birth years 1986-88) of VLBW individuals and term born controls with normal birth weight, the main aim was to examine group differences in memory function and hippocampal volumes at age 26 years. We also explored hippocampal structurefunction relationships in the VLBW group. Methods: Fifty-two VLBW and 82 control individuals aged 26 years were examined clinically of whom 44 VLBW and 70 controls had high-quality structural cerebral MRI at 3T. The participants were assessed with subtests from Wechsler Memory Scale and Cambridge Neuropsychological Test Automated Battery on verbal, visual and working memory. From the T1 weighted 3D images, hippocampal subfield volumes were estimated in FreeSurfer 6.0. In addition to group comparisons, partial correlations were performed in the VLBW group between hippocampal subfields’ volumes and neonatal risk factors, and between reduced hippocampal subfields’ volumes and performance on the memory tests. Results: Adults with VLBW had lower verbal, visual and working memory scores compared with term born control adults. Absolute hippocampal total and most subfield volumes were smaller in the VLBW group than in the control group, but with different findings in men and women. When adjusting for intracranial volume, left and right cornu ammonis fields and left dentate gyrus were smaller in VLBW women, while the right subiculum was smaller in VLBW men compared with control women and men, respectively. There was a negative correlation between days on mechanical ventilation and volume of the left subiculum in the VLBW group. Smaller left dentate gyrus volume was associated with lower visual memory performance in the VLBW group. Conclusions: Adults born preterm with VLBW had lower performance on memory tests and smaller hippocampi compared with term born controls, and volume of dentate gyrus was associated with visual memory. Hippocampal subfield volumes seem to be differently affected following preterm birth in VLBW men and women

Relationship between hippocampal subfield volumes and memory function in adults born preterm with very low birth weight (VLBW)

Background:Being born preterm with very low birth weight (VLBW) is related to aberrant brain development. Hippocampus is a brain region particularly vulnerable to injury, for instance from consequences following preterm birth. The hippocampus is a complex structure with distinct subfields related to specific memory functions which are differently affected by neuropathological conditions. The relationship between deviations in hippocampal subfields and memory function has not been studied in adults born preterm with VLBW previously. Aims: In this long-term follow-up study of a geographically based cohort (birth years 1986-88) of VLBW individuals and term born controls with normal birth weight, the main aim was to examine group differences in memory function and hippocampal volumes at age 26 years. We also explored hippocampal structurefunction relationships in the VLBW group. Methods: Fifty-two VLBW and 82 control individuals aged 26 years were examined clinically of whom 44 VLBW and 70 controls had high-quality structural cerebral MRI at 3T. The participants were assessed with subtests from Wechsler Memory Scale and Cambridge Neuropsychological Test Automated Battery on verbal, visual and working memory. From the T1 weighted 3D images, hippocampal subfield volumes were estimated in FreeSurfer 6.0. In addition to group comparisons, partial correlations were performed in the VLBW group between hippocampal subfields’ volumes and neonatal risk factors, and between reduced hippocampal subfields’ volumes and performance on the memory tests. Results: Adults with VLBW had lower verbal, visual and working memory scores compared with term born control adults. Absolute hippocampal total and most subfield volumes were smaller in the VLBW group than in the control group, but with different findings in men and women. When adjusting for intracranial volume, left and right cornu ammonis fields and left dentate gyrus were smaller in VLBW women, while the right subiculum was smaller in VLBW men compared with control women and men, respectively. There was a negative correlation between days on mechanical ventilation and volume of the left subiculum in the VLBW group. Smaller left dentate gyrus volume was associated with lower visual memory performance in the VLBW group. Conclusions: Adults born preterm with VLBW had lower performance on memory tests and smaller hippocampi compared with term born controls, and volume of dentate gyrus was associated with visual memory. Hippocampal subfield volumes seem to be differently affected following preterm birth in VLBW men and women

Harnessing the power of the new SMP cluster architecture

In 1993, members of our team collaborated with Silicon Graphics to perform the first full-scale demonstration of the computational power of the SMP cluster supercomputer architecture. That demonstration involved the simulation of homogeneous, compressible turbulence on a uniform grid of a billion cells, using our PPM gas dynamics code. This computation was embarrassingly parallel, the ideal test case, and it achieved only 4.9 Gflop/s performance, slightly over half that achievable by this application on the most expensive supercomputers of that day. After four to five solid days of computation, when the prototype machine had to be dismantled, the simulation was only about 20% completed. Nevertheless, this computation gave us important new insights into compressible turbulence and also into a powerful new mode of cost-effective, commercially sustainable supercomputing [S]. In the intervening 6 years, the SMP cluster architecture has become a fundamental strategy for several large supercomputer centers in the US, including the DOE's ASCI centers at Los Alamos National Laboratory and at the Lawrence Livermore National Laboratory and the NSF's center NCSA at the University of Illinois. This SMP cluster architecture now underlies product offerings at the high-end of performance from SGI, IBM, and HP, among others. Nevertheless, despite many successes, it is our opinion that the computational science community is only now beginning to exploit the full promise of these new computing platforms. In this paper, we will briefly discuss two key architectural issues, vector computing and the flat multiprocessor architecture, which continue to drive spirited discussions among computational scientists, and then we will describe the hierarchical shared memory programming paradigm that we feel is best suited to the creative use of SMP cluster systems. Finally, we will give examples of recent large-scale simulations carried out by our team on these kinds of systems and point toward the still more challenging work which we foresee in the near future