Generalized Electrical Substitution Methods and Detectors for Absolute Optical Power Measurements.

We have developed generalized methods for electrical substitution optical measurements, as well as cryogenic detectors which can be used to implement them. The new methods detailed here enable measurement of arbitrary periodic waveforms by an electrical substitution radiometer (ESR), which means that spectral and dynamic optical power can be absolutely calibrated directly by a primary standard detector. Cryogenic ESRs are not often used directly by researchers for optical calibrations due to their slow response times and cumbersome operation. We describe two types of ESRs with fast response times, including newly developed cryogenic bolometers with carbon nanotube absorbers, which are manufacturable by standard microfabrication techniques. These detectors have response times near 10 ms, spectral coverage from the ultraviolet to far-infrared, and are ideal for use with generalized electrical substitution. In our first tests of the generalized electrical substitution method with FTS, we have achieved uncertainty in detector response of 0.13 % (k=1) and total measurement uncertainty of 1.1 % (k=1) in the mid-infrared for spectral detector responsivity calibrations. The generalized method and fast detectors greatly expand the range of optical power calibrations which can be made using a wideband primary standard detector, which can shorten calibration chains and improve uncertainties.

Development of electrical substitution Fourier transform spectrometry for absolute optical power measurements.

We have demonstrated the first continuous-scan electrical substitution Fourier transform spectrometer (ES-FTS), which serves initially as an apparatus for absolute spectral responsivity calibrations of detectors over the wavelength range from 1.5 µm to 11 µm. We present data on the realization of a spectral detector-comparator system with high accuracy, high dynamic range, high spectral resolution and fast measurement in the infrared region, which is tied directly to an absolute power scale through electrical substitution. The ES-FTS apparatus employs a commercial Fourier transform spectrometer and a custom electrical substitution bolometer detector to enable spectrally-resolved absolute optical power measurements. A generalization of electrical substitution techniques enables determination of the voltage waveform that must be applied to the bolometer's electrical heater to cancel the optical signal from a Michelson interferometer in order to quantify the time-dependent optical power incident on the bolometer. The noise floor of the electrical substitution bolometer is on the order of 10 pW/Hz½ and its response is expected to be linear from the noise floor to 1 mW. A direct comparison between a pyroelectric standard detector and the ES-FTS has been performed, and experimental results reported here show great potential for this technique.

Genome-wide association study identifies a novel locus for cannabis dependence.

Despite moderate heritability, only one study has identified genome-wide significant loci for cannabis-related phenotypes. We conducted meta-analyses of genome-wide association study data on 2080 cannabis-dependent cases and 6435 cannabis-exposed controls of European descent. A cluster of correlated single-nucleotide polymorphisms (SNPs) in a novel region on chromosome 10 was genome-wide significant (lowest P=1.3E-8). Among the SNPs, rs1409568 showed enrichment for H3K4me1 and H3K427ac marks, suggesting its role as an enhancer in addiction-relevant brain regions, such as the dorsolateral prefrontal cortex and the angular and cingulate gyri. This SNP is also predicted to modify binding scores for several transcription factors. We found modest evidence for replication for rs1409568 in an independent cohort of African American (896 cases and 1591 controls; P=0.03) but not European American (EA; 781 cases and 1905 controls) participants. The combined meta-analysis (3757 cases and 9931 controls) indicated trend-level significance for rs1409568 (P=2.85E-7). No genome-wide significant loci emerged for cannabis dependence criterion count (n=8050). There was also evidence that the minor allele of rs1409568 was associated with a 2.1% increase in right hippocampal volume in an independent sample of 430 EA college students (fwe-P=0.008). The identification and characterization of genome-wide significant loci for cannabis dependence is among the first steps toward understanding the biological contributions to the etiology of this psychiatric disorder, which appears to be rising in some developed nations.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Evidence of CNIH3 involvement in opioid dependence.

Opioid dependence, a severe addictive disorder and major societal problem, has been demonstrated to be moderately heritable. We conducted a genome-wide association study in Comorbidity and Trauma Study data comparing opioid-dependent daily injectors (N=1167) with opioid misusers who never progressed to daily injection (N=161). The strongest associations, observed for CNIH3 single-nucleotide polymorphisms (SNPs), were confirmed in two independent samples, the Yale-Penn genetic studies of opioid, cocaine and alcohol dependence and the Study of Addiction: Genetics and Environment, which both contain non-dependent opioid misusers and opioid-dependent individuals. Meta-analyses found five genome-wide significant CNIH3 SNPs. The A allele of rs10799590, the most highly associated SNP, was robustly protective (P=4.30E-9; odds ratio 0.64 (95% confidence interval 0.55-0.74)). Epigenetic annotation predicts that this SNP is functional in fetal brain. Neuroimaging data from the Duke Neurogenetics Study (N=312) provide evidence of this SNP's in vivo functionality; rs10799590 A allele carriers displayed significantly greater right amygdala habituation to threat-related facial expressions, a phenotype associated with resilience to psychopathology. Computational genetic analyses of physical dependence on morphine across 23 mouse strains yielded significant correlations for haplotypes in CNIH3 and functionally related genes. These convergent findings support CNIH3 involvement in the pathophysiology of opioid dependence, complementing prior studies implicating the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate system.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Estimating the heritability of reporting stressful life events captured by common genetic variants.

BACKGROUND: Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. RESULTS: A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). CONCLUSIONS: These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.

Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28.

Linkage disequilibrium (LD), or the non-random association of alleles, is poorly understood in the human genome. Population genetic theory suggests that LD is determined by the age of the markers, population history, recombination rate, selection and genetic drift. Despite the uncertainties in determining the relative contributions of these factors, some groups have argued that LD is a simple function of distance between markers. Disease-gene mapping studies and a simulation study gave differing predictions on the degree of LD in isolated and general populations. In view of the discrepancies between theory and experimental observations, we constructed a high-density SNP map of the Xq25-Xq28 region and analysed the male genotypes and haplotypes across this region for LD in three populations. The populations included an outbred European sample (CEPH males) and isolated population samples from Finland and Sardinia. We found two extended regions of strong LD bracketed by regions with no evidence for LD in all three samples. Haplotype analysis showed a paucity of haplotypes in regions of strong LD. Our results suggest that, in this region of the X chromosome, LD is not a monotonic function of the distance between markers, but is more a property of the particular location in the human genome.

Best Practice Guidelines for Pre-Launch Characterization and Calibration of Instruments for Passive Optical Remote Sensing.

The pre-launch characterization and calibration of remote sensing instruments should be planned and carried out in conjunction with their design and development to meet the mission requirements. The onboard calibrators such as blackbodies and the sensors such as spectral radiometers should be characterized and calibrated using SI traceable standards. In the case of earth remote sensing, this allows inter-comparison and intercalibration of different sensors in space to create global time series of climate records of high accuracy where some inevitable data gaps can be easily bridged. The recommended best practice guidelines for this pre-launch effort is presented based on experience gained at National Institute of Standards and Technology (NIST), National Aeronautics and Space Administration (NASA) and National Oceanic and Atmospheric Administration (NOAA) programs over the past two decades. The currently available radiometric standards and calibration facilities at NIST serving the remote sensing community are described. Examples of best practice calibrations and intercomparisons to build SI (international System of Units) traceable uncertainty budget in the instrumentation used for preflight satellite sensor calibration and validation are presented.

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence.

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

Sources of Differences in On-Orbital Total Solar Irradiance Measurements and Description of a Proposed Laboratory Intercomparison.

There is a 5 W/m(2) (about 0.35 %) difference between current on-orbit Total Solar Irradiance (TSI) measurements. On 18-20 July 2005, a workshop was held at the National Institute of Standards and Technology (NIST) in Gaithersburg, Maryland that focused on understanding possible reasons for this difference, through an examination of the instrument designs, calibration approaches, and appropriate measurement equations. The instruments studied in that workshop included the Active Cavity Radiometer Irradiance Monitor III (ACRIM III) on the Active Cavity Radiometer Irradiance Monitor SATellite (ACRIMSAT), the Total Irradiance Monitor (TIM) on the Solar Radiation and Climate Experiment (SORCE), the Variability of solar IRradiance and Gravity Oscillations (VIRGO) on the Solar and Heliospheric Observatory (SOHO), and the Earth Radiation Budget Experiment (ERBE) on the Earth Radiation Budget Satellite (ERBS). Presentations for each instrument included descriptions of its design, its measurement equation and uncertainty budget, and the methods used to assess on-orbit degradation. The workshop also included a session on satellite- and ground-based instrument comparisons and a session on laboratory-based comparisons and the application of new laboratory comparison techniques. The workshop has led to investigations of the effects of diffraction and of aperture area measurements on the differences between instruments. In addition, a laboratory-based instrument comparison is proposed that uses optical power measurements (with lasers that underfill the apertures of the TSI instruments), irradiance measurements (with lasers that overfill the apertures of the TSI instrument), and a cryogenic electrical substitution radiometer as a standard for comparing the instruments. A summary of the workshop and an overview of the proposed research efforts are presented here.

Spectrally Tunable Sources for Advanced Radiometric Applications.

A common radiometric platform for the development of application-specific metrics to quantify the performance of sensors and systems is described. Using this platform, sensor and system performance may be quantified in terms of the accuracy of measurements of standardized sets of source distributions. The prototype platform consists of spectrally programmable light sources that can generate complex spectral distributions in the ultraviolet, visible and short-wave infrared regions for radiometric, photometric and colorimetric applications. In essence, the programmable spectral source is a radiometric platform for advanced instrument characterization and calibration that can also serve as a basis for algorithm testing and instrument comparison.

A sex-adjusted and age-adjusted genome screen for nested alcohol dependence diagnoses.

Alcohol dependence is a complex disorder with a substantial genetic contribution to susceptibility. The Collaborative Study on the Genetics of Alcoholism is a multi-site study whose purpose is to detect, localize, and characterize genes contributing to this susceptibility. Previous linkage analyses of the trait of alcohol dependence in Collaborative Study on the Genetics of Alcoholism have used affected sib-pair methods with a dichotomous phenotype definition. In contrast, the analysis in this paper uses a sex-adjusted and age-adjusted multiple threshold liability model. The use of such a model, in that it includes unaffected as well as as affected subjects and in that it utilizes the differential severity of a diagnosis scale, should heuristically be more powerful than a straight affected sib-pair analysis. Three regions of interest are found on chromosome 1 (lod 5.17), chromosome 4 (lod 3.46), and chromosome 8 (lod 4.31). The region on chromosome 1 near the marker D1S532 is in the region previously reported as linked to alcohol dependence and correlated phenotypes in this dataset. The region on chromosome 4 near the alcohol dehydrogenase gene cluster has been reported to be linked to alcohol dependence in other studies, as well as to the alcohol consumption phenotype 'Maximum Number of Drinks in a 24-Hour Period' in this dataset. The region on chromosome 8 near the marker D8S1988 is homologous to a section of rat chromosome 5 to which an alcohol consumption phenotype has been linked.

Stability of psychiatric diagnoses. An application to the affective disorders.

In the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression study, data were collected on 2226 first-degree relatives of 612 probands. A second, "blind" reassessment of all relatives was attempted 6 years after the initial evaluation. We report on a final sample of 1629 relatives assessed twice using the Schedule for Affective Disorders and Schizophrenia-Lifetime version. We summarize methods for using stability of diagnosis to model the relationship between clinical covariates and the probability of being a true case. Moreover, we define an index of caseness that can be used to narrow the criteria for who is a case. Of those positive for major depressive disorder at initial evaluation, 74% were positive (on a lifetime basis) at follow-up (ie, were stable). There is a gradient: 48% of those who had three symptoms and no treatment were stable, compared with 96% of those with eight symptoms and treatment. For major depressive disorder, we found the caseness index for those with lifetime mania more severe than that of nonbipolar patients, with those who had hypomania being intermediate. A hierarchical analysis indicated that bipolar I tends to be diagnosed as schizoaffective-manic across occasions, and vice versa. This is consistent with the prior familial analyses that suggest these two diagnoses be combined into a single bipolar phenotype. The analysis for major depressive disorder indicates that caseness appears to represent quantitative, rather than qualitative, differences, with no natural cutoff to identify distinct subgroups. Finally, we discuss implications including utility in genetic analyses, estimation of incidence or prevalence allowing for diagnostic error, and examination of cohort effects.

Low levels and lack of predictors of somatotherapy and psychotherapy received by depressed patients.

We examined the treatment of 338 patients with nonbipolar major depressive disorders during the first eight weeks after entry into the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression: Clinical Study. Of the 250 entered as inpatients, 31% received either no antidepressant somatotherapy or very low or unsustained levels, and only 49% received at least 200 mg of imipramine hydrochloride (or its equivalent) for four consecutive weeks. Of these patients, 19% received less than 30 minutes of psychotherapy per week. Among the 88 who entered as outpatients, 29% received no antidepressant somatotherapy; another 24% received very low or unsustained levels; only 19% received at least 200 mg of imipramine hydrochloride or its equivalent for four consecutive weeks. Of these patients, 52% received less than 30 minutes of psychotherapy per week. Only a few clinical factors were found to be predictive of treatment intensity. Very large differences in the amount and type of treatment across the five collaborating university centers do not appear to be related to differences in patient characteristics.

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

Replicated psychometric correlates of schizophrenia.

OBJECTIVE: The authors' goals are to use scales from the MMPI hypothesized in their previous research to be correlates of liability to schizophrenia to differentiate DSM-III schizophrenia from bipolar and unipolar affective illness and to cross-validate these correlates in an independently ascertained sample of patients with Research Diagnostic Criteria (RDC) schizophrenia or affective disorder. METHOD: The criterion sample consisted of 83 patients consecutively admitted to a state-operated community mental health center. Diagnosis of schizophrenia; bipolar disorder, manic; and major depression were assigned by using DSM-III. The replication sample consisted of 60 adults with RDC diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, and unipolar disorder who were parents of children in two samples collected for a study of offspring at high risk for schizophrenia and other psychopathology. After the patients in the criterion sample were classified by logistic regression analysis, the results were used to classify patients in the replication sample. RESULTS: The MMPI indicators had adequate sensitivity, specificity, and predictive power for classifying schizophrenia, and there was a moderately high rate of diagnostic agreement between the MMPI and DSM-III. Cross-validation in the replication sample was successful. Overall, the MMPI index was an adequate inclusion and exclusion criterion not only for DSM-III-defined but also for RDC-defined schizophrenia. CONCLUSIONS: A psychometric index composed of the paranoid schizophrenia, psychoticism, and manifest hostility scales from the MMPI would be a cost-effective measure to increase diagnostic efficacy in future schizophrenia research and clinical practice.

Diagnosis as a covariate in sib-pair linkage analysis.

A novel technique to detect significant covariates in linkage analysis using a logistic regression approach is illustrated. An overall test of linkage is first performed to determine whether there is significant perturbation from the expected 50% sharing in sib pairs. Covariates may include variables defined on the sib pair (multiple levels of diagnosis), covariates defined on the parents (parental diagnosis or gender of the transmitting parent), or indicators of study when analyzing multiple datasets to examine heterogeneity. A detailed example using a hierarchical diagnosis of severe, intermediate, mild, and unaffected is provided. This permits testing whether sib allele sharing differs by level of diagnosis and allows the use of discordant pairs to protect against marker allele misspecification.