Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines.

The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.

Community football teams for people with intellectual disabilities in secure settings: "They take you off the ward, it was like a nice day, and then you get like medals at the end".

BACKGROUND: People with learning disabilities (LD) are particularly vulnerable to mental health and behavioural difficulties, and it has been shown that regular exercise can improve psychosocial well-being as well as physical fitness. This research aims to explore the experiences of men with LD detained in secure settings who have engaged in community football training programmes and identify the benefits of such provision. METHOD: Interviews were conducted with eight patients in a forensic LD service, discussing their experiences of participating in community football. Template analysis was undertaken on the transcripts. RESULTS: Two master themes were identified: physical fitness and psychosocial benefits. As the analysis progressed, new emerging themes were identified around role identity and achievement, as well as extending and refining some of the themes from the original template including fun and belonging. Some anticipated themes were removed from the template entirely. CONCLUSION: The psychosocial benefits of organised community sports programmes far outweigh the physical health benefits. Careful consideration must be given to where on a treatment and rehabilitation pathway non-traditional therapeutic interventions such as sports programmes are offered as an adjunct to specific risk reduction interventions for people with LD in secure settings.

Genome-wide association studies and genomic prediction of breeding values for calving performance and body conformation traits in Holstein cattle.

BACKGROUND: Our aim was to identify genomic regions via genome-wide association studies (GWAS) to improve the predictability of genetic merit in Holsteins for 10 calving and 28 body conformation traits. Animals were genotyped using the Illumina Bovine 50 K BeadChip and imputed to the Illumina BovineHD BeadChip (HD). GWAS were performed on 601,717 real and imputed single nucleotide polymorphism (SNP) genotypes using a single-SNP mixed linear model on 4841 Holstein bulls with breeding value predictions and followed by gene identification and in silico functional analyses. The association results were further validated using five scenarios with different numbers of SNPs. RESULTS: Seven hundred and eighty-two SNPs were significantly associated with calving performance at a genome-wise false discovery rate (FDR) of 5%. Most of these significant SNPs were on chromosomes 18 (71.9%), 17 (7.4%), 5 (6.8%) and 7 (2.4%) and mapped to 675 genes, among which 142 included at least one significant SNP and 532 were nearby one (100 kbp). For body conformation traits, 607 SNPs were significant at a genome-wise FDR of 5% and most of them were located on chromosomes 5 (30%), 18 (27%), 20 (13%), 6 (6%), 7 (5%), 14 (5%) and 13 (3%). SNP enrichment functional analyses for calving traits at a FDR of 1% suggested potential biological processes including musculoskeletal movement, meiotic cell cycle, oocyte maturation and skeletal muscle contraction. Furthermore, pathway analyses suggested potential pathways associated with calving performance traits including tight junction, oxytocin signaling, and MAPK signaling (P < 0.10). The prediction ability of the 1206 significant SNPs was between 78 and 83% of the prediction ability of the BovineSNP50 SNPs for calving performance traits and between 35 and 79% for body conformation traits. CONCLUSIONS: Various SNPs that are significantly associated with calving performance are located within or nearby genes with potential roles in tight junction, oxytocin signaling, and MAPK signaling. Combining the significant SNPs or SNPs within or nearby gene(s) from the HD panel with the BovineSNP50 panel yielded a marginal increase in the accuracy of prediction of genomic estimated breeding values for all traits compared to the use of the BovineSNP50 panel alone.

Physical activity and cancer-specific mortality in the NIH-AARP Diet and Health Study cohort.

Higher physical activity levels have been associated with a lower risk of developing various cancers and all-cancer mortality, but the impact of pre-diagnosis physical activity on cancer-specific death has not been fully characterized. In the prospective National Institutes of Health-AARP Diet and Health Study with 293,511 men and women, we studied prediagnosis moderate to vigorous intensity leisure time physical activity (MVPA) in the past 10 years and cancer-specific mortality. Over a median 12.1 years, we observed 15,001 cancer deaths. Using Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for MVPA with cancer mortality overall and by 20 specific cancer sites, adjusting for relevant risk factors. Compared to participants reporting never/rare MVPA, those reporting >7 hr/week MVPA had a lower risk of total cancer mortality (HR = 0.89, 95% CI 0.84-0.94; p-trend <0.001). When analyzed by cancer site-specific deaths, comparing those reporting >7 hr/week of MVPA to those reporting never/rare MVPA, we observed a lower risk of death from colon (HR = 0.70; 95% CI 0.57-0.85; p-trend <0.001), liver (0.71; 0.52-0.98; p-trend = 0.012) and lung cancer (0.84; 0.77-0.92; p-trend <0.001) and a significant p-trend for non-Hodgkins lymphoma (0.80; 0.62-1.04; p-trend = 0.017). An unexpected increased mortality p-trend with increasing MVPA was observed for death from kidney cancer (1.42; 0.98-2.03; p-trend = 0.016). Our findings suggest that higher prediagnosis leisure time physical activity is associated with lower risk of overall cancer mortality and mortality from multiple cancer sites. Future studies should confirm observed associations and further explore timing of physical activity and underlying biological mechanisms.

Molecular profiling of pre- and post-treatment pediatric high-grade astrocytomas reveals acquired increased tumor mutation burden in a subset of recurrences.

Diffuse gliomas are a heterogeneous category of primary central nervous system tumors. Due to their infiltrative growth precluding complete surgical resection, most diffuse high-grade gliomas are treated with adjuvant chemotherapy and radiation. Recurrent/progressive diffuse gliomas may show genetic differences when compared to the primary tumors, giving insight into their molecular evolution and mechanisms of treatment resistance. In adult-type diffuse gliomas with or without isocitrate dehydrogenase gene mutations, tumor recurrence/progression can be associated with mutations in genes encoding DNA mismatch repair proteins, leading to a dramatic increase in tumor mutation burden. This phenomenon is closely linked to treatment with the DNA alkylating agent temozolomide, a mainstay of adult diffuse glioma chemotherapeutic management. Post-treatment mismatch repair deficiency and acquired high tumor mutation burden is relatively unexplored in pediatric patients who have recurrent high-grade gliomas. Here, we report a molecular and histological analysis of an institutional cohort of eleven pediatric patients with paired initial and recurrent high-grade astrocytoma samples with intervening temozolomide treatment. We identified three cases with evidence for increased tumor mutation burden at recurrence, including two cases of diffuse hemispheric glioma H3 G34-mutant (one previously reported). We also show that molecular analysis by next-generation DNA sequencing and DNA methylation-based profiling enabled an integrated diagnosis per 2021 World Health Organization criteria in 10 of 11 cases (91%). Our findings indicate that increased tumor mutation burden at post-treatment recurrence is relevant in pediatric-type diffuse high-grade gliomas. Diffuse hemispheric glioma H3 G34-mutant may be particularly susceptible to this phenomenon.

Genome sequence and assembly of Bos indicus.

Cattle are divided into 2 groups referred to as taurine and indicine, both of which have been under strong artificial selection due to their importance for human nutrition. A side effect of this domestication includes a loss of genetic diversity within each specialized breed. Recently, the first taurine genome was sequenced and assembled, allowing for a better understanding of this ruminant species. However, genetic information from indicine breeds has been limited. Here, we present the first genome sequence of an indicine breed (Nellore) generated with 52X coverage by SOLiD sequencing platform. As expected, both genomes share high similarity at the nucleotide level for all autosomes and the X chromosome. Regarding the Y chromosome, the homology was considerably lower, most likely due to uncompleted assembly of the taurine Y chromosome. We were also able to cover 97% of the annotated taurine protein-coding genes.

RNA interference is an antiviral defence mechanism in Caenorhabditis elegans.

RNA interference (RNAi) is an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism that is well defined genetically in Caenorhabditis elegans. RNAi has been postulated to function as an adaptive antiviral immune mechanism in the worm, but there is no experimental evidence for this. Part of the limitation is that there are no known natural viral pathogens of C. elegans. Here we describe an infection model in C. elegans using the mammalian pathogen vesicular stomatitis virus (VSV) to study the role of RNAi in antiviral immunity. VSV infection is potentiated in cells derived from RNAi-defective worm mutants (rde-1; rde-4), leading to the production of infectious progeny virus, and is inhibited in mutants with an enhanced RNAi response (rrf-3; eri-1). Because the RNAi response occurs in the absence of exogenously added VSV small interfering RNAs, these results show that RNAi is activated during VSV infection and that RNAi is a genuine antiviral immune defence mechanism in the worm.

First-Time Disclosure of CVN424, a Potent and Selective GPR6 Inverse Agonist for the Treatment of Parkinson's Disease: Discovery, Pharmacological Validation, and Identification of a Clinical Candidate.

Parkinson's disease (PD) is a chronic and progressive movement disorder with the urgent unmet need for efficient symptomatic therapies with fewer side effects. GPR6 is an orphan G-protein coupled receptor (GPCR) with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway, a striatal brain circuit which shows aberrant hyperactivity in PD patients. Potent and selective GPR6 inverse agonists (IAG) were developed starting from a low-potency screening hit (EC50 = 43 µM). Herein, we describe the multiple parameter optimization that led to the discovery of multiple nanomolar potent and selective GPR6 IAG, including our clinical compound CVN424. GPR6 IAG reversed haloperidol-induced catalepsy in rats and restored mobility in the bilateral 6-OHDA-lesioned rat PD model demonstrating that inhibition of GPR6 activity in vivo normalizes activity in basal ganglia circuitry and motor behavior. CVN424 is currently in clinical development to treat motor symptoms in Parkinson's disease.

Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor.

Antagonism of the glucagon receptor (GCGR) is associated with increased circulating levels of glucagon-like peptide-1 (GLP-1). To investigate the contribution of GLP-1 to the antidiabetic actions of GCGR antagonism, we administered an anti-GCGR monoclonal antibody (mAb B) to wild-type mice and GLP-1 receptor knockout (GLP-1R KO) mice. Treatment of wild-type mice with mAb B lowered fasting blood glucose, improved glucose tolerance, and enhanced glucose-stimulated insulin secretion during an intraperitoneal glucose tolerance test (ipGTT). In contrast, treatment of GLP-1R KO mice with mAb B had little efficacy during an ipGTT. Furthermore, pretreatment with the GLP-1R antagonist exendin-(9-39) diminished the antihyperglycemic effects of mAb B in wild-type mice. To determine the mechanism whereby mAb B improves glucose tolerance, we generated a monoclonal antibody that specifically antagonizes the human GLP-1R. Using a human islet transplanted mouse model, we demonstrated that pancreatic islet GLP-1R signaling is required for the full efficacy of the GCGR antagonist. To identify the source of the elevated GLP-1 observed in GCGR mAb-treated mice, we measured active GLP-1 content in pancreas and intestine from db/db mice treated with anti-GCGR mAb for 8 wk. Elevated GLP-1 in GCGR mAb-treated mice was predominantly derived from increased pancreatic GLP-1 synthesis and processing. All together, these data show that pancreatic GLP-1 is a significant contributor to the glucose-lowering effects observed in response to GCGR antagonist treatment.

Diurnal variation of metabolites in three individual participants.

The circadian system influences virtually all biological functions. Understanding the impact of circadian variation on metabolism may provide insight into mechanisms of circadian-associated disorders and guide the implementation of chrono-therapy. Previous research has reported circadian variation in 7-20% of metabolites in human blood. In this study, untargeted metabolomics profiles were measured using blood of two healthy men and one healthy woman, collected every 2 h for up to 48 h under carefully controlled conditions. The pattern of variation of each metabolite over time was examined on each participant separately, using both one- and two-order harmonic models. A total of 100 of 663 metabolites, representing all metabolite categories, showed diurnal rhythmic concentrations that exceeded the Bonferroni threshold (P < 2.5 × 10-5). Overall, peak times of many metabolites were clustered during the afternoon-midnight, including the majority of amino acids, all peptides, all lysolipids and all phospholipids, whereas the majority of steroids peaked in the morning. We observed substantial inter-individual variation for both peak times and amplitudes in these three subjects. In conclusion, at least 15% of blood metabolites, representing a broad group of biological pathways, exhibit diurnal variation in three participants. The average peak times of most of these metabolites are clustered in morning or afternoon-midnight. Further work is needed to validate and extend this work in more individuals.

MECOM (EVI1) Rearrangements: A Review and Case Report of Two MDS Patients with Complex 3q Inversion/Deletions.

Acute myelogeneous leukemia (AML) with inv(3)/t(3;3)(q13q25) is associated with aberrant expression of the stem-cell regulator MECOM (aka EVI1). Two bone marrow samples received in the OHSU Knight Diagnostic Laboratories (KDL) Cytogenetics Laboratory for chromosomes and FISH for a question of progression of myelodysplastic syndrome (MDS) to AML showed complex abnormalities including a deletion of chromosome 3q, one with del(3)(q13q25) and the other with del(3)(q22q25). In light of the prognostic importance of the activation of the MECOM oncogene and the concurrent inactivation of the GATA2 tumor suppressor that occurs with the classic inversion of chromosome 3q, fluorescence in situ hybridization (FISH) was performed using two different probe designs to better define the 3q deletions in the two cases. Using the Abbott Molecular Laboratories dual fusion MECOM/RPN1 probe, interphase and metaphase cells in both patients showed a variant single fusion (orange/green/fusion) signal pattern consistent with fusion and deletion. Using the three-color (red/green/aqua) Cytocell EVI1 probe, interphase cells in both cases showed a split red/green signal with the aqua signal remaining with the green signal. The distance between the split signals was generally less than is usually seen in the commonly described inverted chromosome 3. These findings are therefore consistent with a complex inversion and concurrent deletion/deletions of chromosome 3q. Thus, the deletion 3q seen in G-banded chromosomes from bone marrow from these two patients is most consistent with the activation of MECOM and the inactivation of GATA2.

Metabolomic Profiling of Long-Term Weight Change: Role of Oxidative Stress and Urate Levels in Weight Gain.

OBJECTIVE: To investigate the association between long-term weight change and blood metabolites. METHODS: Change in BMI over 8.6 ± 3.79 years was assessed in 3,176 females from the TwinsUK cohort (age range: 18.3-79.6, baseline BMI: 25.11 ± 4.35) measured for 280 metabolites at follow-up. Statistically significant metabolites (adjusting for covariates) were included in a multivariable least absolute shrinkage and selection operator (LASSO) model. Findings were replicated in the Cooperative Health Research in the Region of Augsburg (KORA) study (n = 1,760; age range: 25-70, baseline BMI: 27.72 ± 4.53). The study examined whether the metabolites identified could prospectively predict weight change in KORA and in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) study (n = 471; age range: 55-74, baseline BMI: 27.24 ± 5.37). RESULTS: Thirty metabolites were significantly associated with change in BMI per year in TwinsUK using Bonferroni correction. Four were independently associated with weight change in the multivariable LASSO model and replicated in KORA: namely, urate (meta-analysis ß [95% CI] = 0.05 [0.040 to 0.063]; P = 1.37 × 10-19 ), gamma-glutamyl valine (ß [95% CI] = 0.06 [0.046 to 0.070]; P = 1.23 × 10-20 ), butyrylcarnitine (ß [95% CI] = 0.04 [0.028 to 0.051]; P = 6.72 × 10-12 ), and 3-phenylpropionate (ß [95% CI] = -0.03 [-0.041 to -0.019]; P = 9.8 × 10-8 ), all involved in oxidative stress. Higher levels of urate at baseline were associated with weight gain in KORA and PLCO. CONCLUSIONS: Metabolites linked to higher oxidative stress are associated with increased long-term weight gain.

Toward resilient food systems through increased agricultural diversity and local sourcing in the Carolinas.

Biological and agricultural diversity are connected to food security through strengthened resilience to both anthropogenic and natural perturbations. Increased resilience to stress via increased biodiversity has been described in a number of natural systems. Diversity in food production can be considered on the following three levels: (a) genetic diversity as reflected in the range of cultivars which can be selected for production; (b) species diversity, captured through production of a wide range of crops on each farm; and (c) broad ecosystem diversity, described by the diversity of production between farms and within the broader food system. A network of locally based food producers and entrepreneurs provides opportunity for high diversity at each network stage, with increased adaptive capacity and the ability for rapid response to disturbance. We argue that production techniques that use carefully planned diverse plantings, such as biointensive cultivation, increase resilience by increased water use efficiency, yield and nutrient retention while reducing pressure from pests and pathogens. We present a model for a diverse, distributed food system in the North Carolina Piedmont and analyze an existing distributed network by a food hub in South Carolina. Through these models, we argue that a shift in the food network has the potential to increase local food security by having food more reliably available where it is needed and by contributing to local resilience through community economic development. The shift in food production and distribution systems serves multiple goals: When crop loss occurs, other crops still contribute to overall harvest, reducing net loss. Diverse on-farm production can support a more distributed network of food aggregators, processors, and markets than the current approach of large-scale consolidation. Finally, a distributed food supply network supported with diverse agricultural products can increase resilience by providing access to diversified markets for producers and improved food access to consumers with more food choices, while expanding the need for skilled jobs supporting the regionally based food industry.

Angiotensin type 2 receptor neuroprotection against chemical hypoxia is dependent on the delayed rectifier K+ channel, Na+/Ca2+ exchanger and Na+/K+ ATPase in primary cortical cultures.

We have previously reported that angiotensin II (Ang II) protects cortical neurons from chemical-induced hypoxia through activation of the angiotensin type 2 (AT(2)) receptor. Here, we show in mouse primary neuronal cultures that the AT(2) receptor neuroprotection results from the activation of the delayed rectifier K(+) channel as well as the involvement of the Na(+)/Ca(2+) exchanger (NCX) and Na(+)/K(+) ATPase (ATPase). Roles of the K(+) channel, NCX and ATPase were determined using the specific blockers alpha-dendrotoxin, KB-R7943 and ouabain, respectively. Sodium azide (10mM) induced apoptosis in 40% of neurons. Inhibition of the AT(1) receptor with losartan (1 microM) facilitated angiotensin II mediated neuroprotection by reducing sodium azide-induced apoptosis 61.8 +/- 5.6%, while inhibition of the AT(2) receptor with PD123319 (1 microM) showed no neuroprotection. These results suggest that angiotensin II neuroprotection is mediated through the AT(2) receptor and requires inhibition of the AT(1) receptor in order to facilitate its effect. To determine the roles of delayed rectifier K(+) channel, NCX and ATPase cultures were pretreated with alpha-dendrotoxin (10nM), KB-R7943 (100 nM) and ouabain (100 nM), which significantly attenuated AT(2) receptor mediated neuroprotection. These findings further suggest that the mechanism of AT(2) receptor mediated neuroprotection is coupled to activation of the delayed rectifier K(+) channel, NCX and ATPase.

Angiotensin II attenuates chemical hypoxia-induced caspase-3 activation in primary cortical neuronal cultures.

In this study we determined whether caspase-3 is required in mouse cortical neurons for sodium azide-mediated apoptosis. Primary cortical neuronal cultures were treated with a cell permeable caspase-3 inhibitor, DEVD (1 nM-100 fM), prior to sodium azide-induced hypoxia. Treatment with the caspase-3 inhibitor resulted in a dose-dependent decrease in apoptosis, suggesting that sodium azide-induced apoptosis is mediated through a caspase-3 dependent pathway. Levels of cytochrome-c release and caspase-3 cleavage were assayed by Western analysis. Cytochrome-c release and caspase-3 cleavage were observed at 5 h (85.3+/-5.8%) and 8 h (53.4+/-14.9%), respectively. We have previously reported that angiotensin II, acting through the AT(2) receptor subtype, protects cultured mouse cortical neurons from sodium azide-induced apoptosis. We also examined whether the protective effect of angiotensin II is mediated through modulation of caspase-3. Pre-treatment of cells with angiotensin II and the AT(1) receptor antagonist, losartan, reduced levels of sodium azide-induced caspase-3 cleavage by 95.0+/-4.0%. Cells pre-treated with the AT(2) receptor antagonist, PD123319 showed a smaller reduction of caspase-3 cleavage (53.8+/-3.4%). Our findings indicate that sodium azide-induced apoptosis is caspase-3 dependent and that angiotensin II protects cortical neurons from chemical-induced apoptosis by reducing caspase-3 cleavage.

Lifetime adiposity and risk of pancreatic cancer in the NIH-AARP Diet and Health Study cohort.

BACKGROUND: The association of excess body weight across a lifetime with pancreatic cancer has not been examined extensively. OBJECTIVE: We determined the association for body mass index (BMI) at different ages and adiposity duration and gain with incident pancreatic adenocarcinoma in the NIH-AARP Diet and Health Study cohort. DESIGN: Participants aged 50-71 y completed questionnaires at baseline (1995-1996) and 6 months later that queried height and weight history. We calculated HRs and 95% CIs by using Cox proportional hazards models adjusted for age, smoking, sex, and intakes of energy and total fat. RESULTS: Over an average follow-up of 10.5 y, 1206 and 2122 pancreatic cancer cases were identified in the subcohort who completed the second questionnaire (n = 273,975) and the baseline cohort (n = 501,698), respectively. Compared with normal weight, overweight or obesity at ages 18, 35, 50, or >50 y (baseline BMI) was significantly associated with pancreatic cancer, with HRs ranging from 1.15 to 1.53. A longer duration of BMI (in kg/m(2)) >25.0 was significantly associated with pancreatic cancer (overall HR per 10-y increment of duration: 1.06; 95% CI: 1.02, 1.09), with individuals who reported diabetes having the greatest risk (HR per 10-y increment of duration: 1.18; 95% CI: 1.05, 1.32; P-interaction = 0.01) and rates. A substantial gain in adiposity (>10 kg/m(2)) after age 50 y was significantly associated with increased pancreatic cancer risk. The etiologic fraction of pancreatic cancer explained by adiposity at any age was 14% overall and 21% in never smokers. CONCLUSION: Overweight and obesity at any age are associated with increased pancreatic cancer.

Anthropometric measures and physical activity and the risk of lung cancer in never-smokers: a prospective cohort study.

Worldwide, lung cancer in never-smokers is ranked the seventh most common cause of cancer death; however, the etiology of lung cancer in never-smokers is unclear. We investigated associations for body mass index (BMI) at various ages, waist circumference, hip circumference, and physical activity with lung cancer in 158,415 never-smokers of the NIH-AARP Diet and Health Study. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards models. Over 11 years of follow-up, 532 lung cancer cases occurred. The risk estimate for obese (BMI ≥ 30 kg/m(2)) participants at baseline was 1.21 (95%CI = 0.95-1.53) relative to those with a normal BMI between 18.5 ≤ BMI<25.0. Overweight (25.0 ≤ BMI<30.0) at age 18 (HR(overweight-vs-normal) = 1.51;95%CI = 1.01-2.26) and time spent sitting (HR(≥ 3 hrs-vs-<3 hrs) = 1.32;95%CI = 1.00-1.73) was each associated with lung cancer after adjustment for baseline BMI, as was waist (HR(Q4-vs-Q1) = 1.75;95%CI = 1.09-2.79) and hip circumference (HRQ4-vs-Q1 = 0.62;95%CI = 0.39-0.99), after mutual adjustment for each other and baseline BMI. No associations were observed for vigorous activity or television watching. In summary, using a large prospective cohort study, we found no evidence that BMI at baseline or middle age was associated with decreased lung cancer risk in never smokers. If anything, we observed some evidence for positive associations with a larger BMI or waist circumference.

Fast accurate missing SNP genotype local imputation.

BACKGROUND: Single nucleotide polymorphism (SNP) genotyping assays normally give rise to certain percents of no-calls; the problem becomes severe when the target organisms, such as cattle, do not have a high resolution genomic sequence. Missing SNP genotypes, when related to target traits, would confound downstream data analyses such as genome-wide association studies (GWAS). Existing methods for recovering the missing values are successful to some extent - either accurate but not fast enough or fast but not accurate enough. RESULTS: To a target missing genotype, we take only the SNP loci within a genetic distance vicinity and only the samples within a similarity vicinity into our local imputation process. For missing genotype imputation, the comparative performance evaluations through extensive simulation studies using real human and cattle genotype datasets demonstrated that our nearest neighbor based local imputation method was one of the most efficient methods, and outperformed existing methods except the time-consuming fastPHASE; for missing haplotype allele imputation, the comparative performance evaluations using real mouse haplotype datasets demonstrated that our method was not only one of the most efficient methods, but also one of the most accurate methods. CONCLUSIONS: Given that fastPHASE requires a long imputation time on medium to high density datasets, and that our nearest neighbor based local imputation method only performed slightly worse, yet better than all other methods, one might want to adopt our method as an alternative missing SNP genotype or missing haplotype allele imputation method.