STATISTICAL ANALYSES OF HIGH THROUGHPUT GENETICS AND GENOMICS DATA

Mixed effects models are commonly used for modeling the dependence structure between twin pairs in twin studies. However, mixed effects models are extremely computationally intensive for eQTL (expression quantitative trait loci) analysis. To overcome the computational challenge, twin pairs can be randomly split into two independent groups on which multiple linear regression analysis can be performed. In my first topic, a computationally efficient score statistic is proposed to combine non-independent analysis results from the two groups. Genome-wide association studies (GWAS) aim to identify genetic variants associated with complex traits. The standard first pass GWAS analysis where SNPs are tested one at a time may fail to detect associations due to, for example, multiple causal SNPs. Alternatively, regional SNP-set analyses have been established to test the association between a set of SNPs and a phenotype through a mixed effects model where testing the association is equivalent to testing whether one or more of the variance components are equal to 0. However, the null distribution of the likelihood ratio test (LRT) does not follow the conventional 50:50 mixture chi-square distribution in this setting. My second topic investigates the spectral representation of LRT, based on which an empirical resampling procedure is proposed to approximate the null distribution of LRT. When both GWAS and gene expression data are available on the same set of samples, it is natural to add gene expression as a covariate into the SNP-set analysis to jointly model the SNP and transcript association with the trait. One biologically interesting question is whether the complex phenotype is associated with the gene expression conditional on the SNP effects. My last research topic jointly models the association between the gene expression and SNP-set with the trait. Unlike traditional mixed effects models, our model allows the gene expression to be dependent on the random SNP effects since the independent assumption is likely to be violated when the gene expression is also associated with the SNP set. With relaxed independence assumption, we can make valid statistical inference and parameter estimation.Doctor of Philosoph

External modulation method for generating accurate linear optical FMCW

Frequency modulation continuous wave (FMCW) lasers are key components in modern optical imaging. However, current intracavity modulation lasers do not exhibit low-frequency jitter rate and high linearity due to the inherent relaxation oscillations. Although this may be compensated in a direct modulation laser diode using an optoelectronic feedback loop, the available sweep speed is moderately small. In this letter, a special external modulation method is developed to improve the performance of FMCW. Since only the first sideband optical field is used during the entire generation process, phase noise is kept to a minimum and is also independent of the sweep speed. We demonstrate that the linearity and jitter rates do not deteriorate appreciably when the sweep speed is changed over three orders of magnitude, even up to the highest sweep speed of 2.5 GHz/ μs

Fine mapping of dental fluorosis quantitative trait loci in mice

Genetic factors underlie dental fluorosis (DF) susceptibility/resistance. The A/J (DF susceptible) and 129P3/J (DF resistant) strains have been previously used to detect quantitative trait loci (QTL) associated with DF on chromosomes (Chr) 2 and 11. In the present study increased marker density genotyping followed by interval mapping was performed to narrow the QTL intervals and improve the LOD scores. Narrower intervals on Chr 2 where LOD ≥ 6.0 (57–84 cM or ~51 Mb), LOD ≥ 7.0 (62–79 cM or ~32 Mb), and LOD ≥ 8.0 (65–74 cM or ~17 Mb); and on Chr 11 where LOD ≥ 6.0 the interval was 18–51 cM (~53 Mb), LOD ≥ 7.0 (28–48 cM or ~34 Mb), and LOD ≥ 8.0 (31–45 cM or~22 Mb) were obtained. Haplotype analysis between A/J and 129P3/J further reduced QTL intervals. Accn1 was selected as a candidate gene based upon its location near the peak LOD score on Chr 11 and distant homology with the C. elegans fluoride resistance gene flr1. DF severity between Accn1−/− and wildtype mice was not different. The loss of ACCN1 function does not modify DF severity in mice. Narrowing the DF QTL intervals will facilitate additional candidate gene selections and interrogation

Fast eQTL Analysis for Twin Studies

Twin data are commonly used for studying complex psychiatric disorders, and mixed effects models are one of the most popular tools for modeling dependence structures between twin pairs. However, for eQTL (expression quantitative trait loci) data where associations between thousands of transcripts and millions of single nucleotide polymorphisms need to be tested, mixed effects models are computationally inefficient and often impractical. In this paper, we propose a fast eQTL analysis approach for twin eQTL data where we randomly split twin pairs into two groups, so that within each group the samples are unrelated, and we then apply a multiple linear regression analysis separately to each group. A score statistic that automatically adjusts the (hidden) correlation between the two groups is constructed for combining the results from the two groups. The proposed method has well-controlled type I error. Compared to mixed effects models, the proposed method has similar power but drastically improved computational efficiency. We demonstrate the computational advantage of the proposed method via extensive simulations. The proposed method is also applied to a large twin eQTL data from the Netherlands Twin Register

Recovery of Paretic Lower Extremity Loading Ability and Physical Function in the First Six Months After Stroke

To evaluate post-stroke recovery of paretic lower extremity loading, walking ability, and self-reported physical function, and to identify subject characteristics associated with recovery

Interfrontal Bone Among Inbred Strains of Mice and QTL Mapping

The interfrontal bone (IF) is a minor skeletal trait residing between the frontal bones. IF is considered a quasi-continuous trait. Genetic and environmental factors appear to play roles in its development. The mechanism(s) underlying IF bone development are poorly understood. We sought to survey inbred strains of mice for the prevalence of IF and to perform QTL mapping studies. Archived mouse skulls from a mouse phenome project (MPP) were available for this study. 27 inbred strains were investigated with 6–20 mice examined for each strain. Skulls were viewed dorsally and the IF measured using a zoom stereomicroscope equipped with a calibrated reticle. A two generation cross between C3H/HeJ and C57BL/6J mice was performed to generate a panel of 468 F2 mice. F2 mice were phenotyped for presence or absence of IF bone and among mice with the IF bone maximum widths and lengths were measured. F2 mice were genotyped for 573 SNP markers informative between the two strains and subjected to linkage map construction and interval QTL mapping. Results: Strain dependent differences in the prevalence of IF bones were observed. Overall, 77.8% or 21/27, of the inbred strains examined had IF bones. Six strains (C3H/HeJ, MOLF/EiJ, NZW/LacJ, SPRET/EiJ, SWR/J, and WSB/EiJ) lack IF bones. Among the strains with IF bones, the prevalence ranged from 100% for C57BL/6J, C57/LJ, CBA/J, and NZB/B1NJ and down to 5% for strains such as CAST/Ei. QTL mapping for IF bone length and widths identifies for each trait one strong QTL detected on chromosome 14 along with several other significant QTLs on chromosomes 3, 4, 7, and 11. Strain dependent differences in IF will facilitate investigation of genetic factors contributing to IF development. IF bone formation may be a model to understand intrasutural bone formation

The Distribution Pattern of Sediment Archaea Community of the Poyang Lake, the Largest Freshwater Lake in China

Archaea plays an important role in the global geobiochemical circulation of various environments. However, much less is known about the ecological role of archaea in freshwater lake sediments. Thus, investigating the structure and diversity of archaea community is vital to understand the metabolic processes in freshwater lake ecosystems. In this study, sediment physicochemical properties were combined with the results from 16S rRNA clone library-sequencing to examine the sediment archaea diversity and the environmental factors driving the sediment archaea community structures. Seven sites were chosen from Poyang Lake, including two sites from the main lake body and five sites from the inflow river estuaries. Our results revealed high diverse archaea community in the sediment of Poyang Lake, including Bathyarchaeota (45.5%), Euryarchaeota (43.1%), Woesearchaeota (3.6%), Pacearchaeota (1.7%), Thaumarchaeota (1.4%), suspended Lokiarchaeota (0.7%), Aigarchaeota (0.2%), and Unclassified Archaea (3.8%). The archaea community compositions differed among sites, and sediment property had considerable influence on archaea community structures and distribution, especially total organic carbon (TOC) and metal lead (Pb) (p<0.05). This study provides primary profile of sediment archaea distribution in freshwater lakes and helps to deepen our understanding of lake sediment microbes

Efficacy and safety of filgotinib in methotrexate-naive patients with rheumatoid arthritis with poor prognostic factors: post hoc analysis of FINCH 3

OBJECTIVE: This analysis evaluated efficacy and safety of filgotinib, a Janus-associated kinase 1-preferential inhibitor, in methotrexate (MTX)-naive patients with rheumatoid arthritis (RA) with multiple poor prognostic factors (PPFs). METHODS: This was a post hoc analysis of the phase III, randomised, double-blind, active-controlled, FINCH 3 study (clinicaltrials.gov NCT02886728). Patients received once-daily oral filgotinib 200 or 100 mg plus once-weekly oral MTX ≤20 mg (FIL200 + MTX and FIL100 + MTX), filgotinib 200 mg monotherapy (FIL200), or oral MTX monotherapy (MTX-mono) for up to 52 weeks. PPFs investigated were seropositivity for rheumatoid factor or anticyclic citrullinated peptide antibodies, high-sensitivity C reactive protein (CRP) ≥4 mg/L, Disease Activity Score in 28 joints with CRP (DAS28(CRP)) >5.1, and presence of erosions. Filgotinib efficacy and safety in patients with all four PPFs at baseline were explored versus MTX-mono within this subgroup and compared informally with the overall population. RESULTS: Of 1249 patients in FINCH 3, 510 (40.8%) had all PPFs. Efficacy of FIL200 + MTX among these patients was comparable to the overall population, with higher rates of 20%/50%/70% improvement from baseline by American College of Rheumatology criteria, DAS28(CRP) <2.6, and remission; greater improvement in physical function and pain; and better inhibition of structural damage relative to MTX-mono. FIL100 + MTX and FIL200 were not consistently more efficacious versus MTX-mono. Safety of filgotinib in patients with PPFs was comparable to the overall population; no new safety signals were observed. CONCLUSION: FIL200 + MTX efficacy and safety in patients with multiple PPFs were similar to the overall population

Fluoride Modulates Parathyroid Hormone Secretion in vivo and in vitro

The study objective was to investigate fluoride’s effects on iPTH secretion. Thryo-parathyroid complexes (TPCs) from C3H (n=18) and B6 (n=18) mice were cultured in Ca2+ optimized medium. TPCs were treated with 0, 250 or 500µM NaF for 24hrs and secreted iPTH assayed by ELISA. C3H (n=78) and B6 (n=78) mice were gavaged once with distilled or with fluoride (0.001mg [F−]/g body weight) water. At serial time points (0.5–96hrs) serum iPTH, fluoride, total calcium, phosphorus and magnesium levels were determined. Expression of genes involved in mineral regulation via bone-parathyroid-kidney (BPK) axis such as: Pth, Casr, Vdr, Pthlh, Fgf23, αKlotho, Fgf1rc, Tnfs11, Pth1r, Slc34a1, Slc9a3r1, Clcn5 and Pdzk1 were determined in TPCs, humerii and kidneys at 24hrs. An in vitro decrease in iPTH was seen in C3H and B6 TPC at 500µM (p<0.001). In vivo levels of serum fluoride peaked at 0.5hr in both C3H (p=0.002) and B6 (p=0.01). In C3H, iPTH decreased at 24hrs (p<0.0001) returning to baseline at 48hrs. In B6, iPTH increased at 12hrs (p<0.001) returning to baseline at 24hrs. Serum total calcium, phosphorus and magnesium did not change significantly. Pth, Casr, αKlotho, Fgf1rc, Vdr and Pthlh were significantly up-regulated in C3H TPC as compared to B6. Conclusions, fluoride’s effects on TPC in vitro were equivalent between the two mouse strains. However, fluoride demonstrated an early strain dependent effect on iPTH secretion in vivo. Both strains demonstrated a differences in the expression of genes involved in BPK axis suggesting a possible role in physiologic handling of fluoride