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Background Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated heritability, and the prevalence of asthma differs between populations and geographic regions. Robust association analyses incorporating different genetic ancestries and whole-genome sequencing data may identify novel genetic associations. Methods We performed family-based genome-wide association analyses of childhood-onset asthma based on whole-genome sequencing (WGS) data for the ‘The Genetic Epidemiology of Asthma in Costa Rica’ study (GACRS) and the Childhood Asthma Management Program (CAMP). Based on parent–child trios with children diagnosed with asthma, we performed a single variant analysis using an additive and a recessive genetic model and a region-based association analysis of low-frequency and rare variants. Results Based on 1180 asthmatic trios (894 GACRS trios and 286 CAMP trios, a total of 3540 samples with WGS data), we identified three novel genetic loci associated with childhood-onset asthma: rs4832738 on 4p14 ($P=1.72\ast{10}^{-9}$, recessive model), rs1581479 on 8p22 ($P=1.47\ast{10}^{-8}$, additive model) and rs73367537 on 10q26 ($P=1.21\ast{10}^{-8}$, additive model in GACRS only). Integrative analyses suggested potential novel candidate genes underlying these associations: PGM2 on 4p14 and FGF20 on 8p22. Conclusion Our family-based whole-genome sequencing analysis identified three novel genetic loci for childhood-onset asthma. Gene expression data and integrative analyses point to PGM2 on 4p14 and FGF20 on 8p22 as linked genes. Furthermore, region-based analyses suggest independent potential low-frequency/rare variant associations on 8p22. Follow-up analyses are needed to understand the functional mechanisms and generalizability of these associations.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

BackgroundSex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not been extensively analysed for atopy-related markers including allergy skin tests, IgE and eosinophils in asthmatic children.MethodsWe performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole-genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations.ResultsSingle nucleotide polymorphism (SNP) rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (pinteraction=9.08×10−10) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (pinteraction=0.0058). Gene expression ofZNF33B(zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys.ConclusionsWe report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role forZNF33Bshould be studied further as an important driver of sex-divergent features of atopy in childhood asthma.

Under the heading of reliability, most textbooks refer to classical reliability indexes as appropriate measures for determining interrater agreement. It is argued that interrater agreement is a psychometric property that is theoretically different from classical reliability. Interrater agreement indexes measure the degree to which two or more raters agree on the observation of one or more behaviors on one or more subjects and are not theoretically related to classical test theory. A detailed set of formulas is presented to illustrate a set of algebraically equivalent rater agreement indexes that are intended to provide the educational and psychological researcher and practitioner with a practical means of establishing a measure of rater agreement. The formulas are illustrated with a data set. The formulas can be used for dichotomous and continuous data for two or more raters, on one or more subjects, on one or more behaviors. These rater agreement indexes are useful with performance assessments such as observations, porfolios, performance evaluations, essay writing evaluations, authentic assessments, and so on, where multiple facets impact rater agreement.

For finite populations, differences in individual histories can cause between-locus allelic dependencies even for unlinked loci. The main motivation for this study is to quantify the effect of such dependencies on genotypic match probabilities. We compare the two-locus match probability, the probability that two individuals (four gametes) chosen at random will have the same genotype at both loci, with the probability computed as the product of the one-locus match probabilities. It is demonstrated that the product rule probability always underestimates the two-locus match probability. For highly mutable minisatellite loci, these probabilities can differ by an order of magnitude or more. A simplified three-locus problem is explored, providing evidence that the degree of under-estimation worsens for more loci.

While there is now a large and rapidly growing literature on the study of direct limits of subalgebras of finite dimensional C*-algebras, the focus in almost every paper on the subject has been on systems with embeddings which have *-extensions to the generated C*-algebra. One notable exception is the paper by Power [PI]. The purpose of this note is to extend the study of systems which are not *-extendible and to produce examples which illustrate some new phenomena.

It is shown that if the invariant subspace lattice of a reflexive algebra CT, acting on a separable Hilbert space, is both commutative and completely distributive, then the algebra generated by the rank-one operators of &T is dense in &T is any of the strong, weak, ultrastrong or ultraweak topologies. Some related density results are also obtained. The main purpose of this note is to clarify the role of the rank-one operators in a reflexive algebra with a (commutative) completely distributive invariant subspace lattice. A complete lattice is completely distributive if it permits distribution of the lattice operations over families ofarbitrary cardinality (see below for a precise definition). Every nest, i.e. every totally ordered subspace lattice, is completely distributive. For a subspace lattice, the property of being completely distributive is intimately related to the presence of rank-one operators in the associated reflexive algebra. For a given reflexive algebra C, we will refer to the subalgebra generated by the rank-one operators in d as the rank-one subalgebra of e. In [10] it was shown that if the rank-one subalgebra of d( is strongly dense in 6 then the lattice of invariant subspaces of ( is completely distributive. In the converse direction, it was known (see [9]) that the rank-one subalgebra of a reflexive algebra with completely distributive invariant subspace lattice was big enough to determine the lattice and the natural question to ask was: is it big enough to determine the algebra? Specifically, is the rank-one subalgebra of a reflexive algebra with completely distributive invariant subspace lattice strongly dense in the algebra? This was known to be true for nest algebras [2] and also in the case where the underlying Hilbert space was finite-dimensional. Subsequently, Lambrou [7] showed that complete distributivity of a subspace lattice implied a condition somewhat weaker than the desired strong density. Here we show that the answer is affirmative if the additional requirement of commutativity is imposed on the invariant subspace lattice. Some related density results are obtained. Specifically, our main result is that if the invariant subspace lattice of a reflexive algebra C6, acting on a separable Hilbert space, is commutative and completely distributive, then the rank-one subalgebra of C is dense in e in any of the strong, weak, ultrastrong or ultraweak topologies. As a consequence, we show that if the invariant subspace lattice of a reflexive algebra e is Received by the editors January 19, 1983. This paper was presented (by the first author) in the Special Session of Operator Algebras in Operator Theory, Annual Meeting of the A.M.S., January 1983. 1980 Mathematics Subject Classification. Primary 47D25. ?l 983 American Mathematical Society 0002-9939/83 $1.00 + $.25 per page

Arveson has recently generalized an important result of Andersen’s about continuous nests to a larger class of lattices. Andersen’s result is a base for much of the recent interesting work on compact perturbations and similarity of nest algebras. This paper investigates further the structure of such lattices. It is shown that the ordered group lattices with Σ \Sigma -continuous measures introduced by Arveson are completely distributive. This immediately implies various nice properties of Alg L {\text {Alg}}\mathcal {L} , the associated algebra of operators leaving such a lattice L \mathcal {L} invariant. (Among these are the fact that the rank one operators in Alg L {\text {Alg}}\mathcal {L} are dense in Alg L {\text {Alg}}\mathcal {L} and that Alg L + K {\text {Alg}}\mathcal {L} + \mathcal {K} is norm closed where K \mathcal {K} denotes the compact operators.)