PASTRY: achieving balanced power for detecting risk and protective minor alleles in meta-analysis of association studies with overlapping subjects.

BACKGROUND: Meta-analysis is a statistical method that combines the results of multiple studies to increase statistical power. When multiple studies participating in a meta-analysis utilize the same public dataset as controls, the summary statistics from these studies become correlated. To solve this challenge, Lin and Sullivan proposed a method to provide an optimal test statistic adjusted for the correlation. This method quickly became the standard practice. However, we identified an unexpected power asymmetry phenomenon in this standard framework. This can lead to unbalanced power for detecting protective minor alleles and risk minor alleles. RESULTS: We found that the power asymmetry of the current framework is mainly due to the errors in approximating the correlation term. We then developed a meta-analysis method based on an accurate correlation estimator, called PASTRY (A method to avoid Power ASymmeTRY). PASTRY outperformed the standard method on both simulated and real datasets in terms of the power symmetry. CONCLUSIONS: Our findings suggest that PASTRY can help to alleviate the power asymmetry problem. PASTRY is available at https://github.com/hanlab-SNU/PASTRY .

A Descriptive Study of Treatment of Pain in Acute Care for Patients Living With Dementia.

BACKGROUND: During the hospital stay pain is very common among patients living with dementia. METHODS: Descriptive data was obtained from chart review and included age, gender, race, comorbidities and admitting diagnosis. AIMS: The purpose of this study was to describe pain among patients living with dementia, the use of pharmacologic and nonpharmacologic treatment, and to compare treatments among those with and without pain. DESIGN: This was a descriptive study using baseline data from the first 233 participants from the study "Testing the Implementation of Function Focused Care for Acute Care Using the Evidence Integration Triangle (FFC-AC-EIT)". PARTICIPANTS/SUBJECTS: The mean age of participants was 83 (SD=5) and the majority was female (65%) and White (67%) with evidence of dementia (based on a mean Saint Louis University Mental Status Test = 7.23, SD=5.85). RESULTS: Overall 98 (42%) participants had pain and 135 (58%) no pain. Only 14 (6%) participants received no nonpharmacologic or pharmacologic interventions for pain and five of these individuals had pain. The most frequently used pharmacologic intervention among all participants was acetaminophen (n = 121, 52%), then tramadol (n = 19, 8%). Comfort measures and general nonpharmacologic approaches were the most frequently used non-pharmacologic approaches, then physical activity and therapeutic communication. From admission to discharge, there was a trend towards a decrease in pain. There was more use of opioids, physical activity, and therapeutic communication in the no pain group versus the pain group. CONCLUSIONS: The majority of hospitalized medical patients living with dementia were treated for pain, but an ongoing focus is needed to assure optimal pain management for all patients.

Relationship between PASI and FDLQI in paediatric psoriasis, and treatments used in daily clinical practice.

BACKGROUND/OBJECTIVES: Psoriasis is a chronic, inflammatory skin disease that affects 0.71% of children. Skin diseases can have a significant impact on quality of life not only for the children affected by psoriasis, but also for their parents and carers. This study aimed to achieve more insight into the quality of life (QOL) of family of paediatric patients with psoriasis, and to investigate whether disease severity scores correlate with Family Dermatology Life Quality Index (FDLQI) scores. In addition, we also observed the treatments used to treat paediatric psoriasis in daily clinical practice. METHODS: Patients with paediatric psoriasis aged 16 and under who visited our outpatient department were included. Baseline Psoriasis Area and Severity Index (PASI) and FDLQI were measured and analysed. RESULTS: Of 157 patients were included in the study. Median PASI was 4.2 (IQR 2.6-6.9), and the median FDLQI was 12 (IQR 7-17). The correlation coefficient between PASI and FDLQI was 0.44 (P < 0.001). Burden of care was the highest scoring item on the FDLQI, followed by emotional impact. 146 patients were treated with topical therapy with a mean improvement in PASI of 3.92. 19 patients underwent phototherapy, and 19 underwent systemic therapy. CONCLUSIONS: In this largest study to date studying the impact of PASI on FDLQI, disease severity was found to be strongly associated with adverse quality of life of family members of paediatric psoriasis patients.

Use of narrowband ultraviolet B (NBUVB) in paediatric psoriasis: A systematic literature review and meta-analysis.

BACKGROUND/ OBJECTIVES: Phototherapy is used commonly in adult psoriasis; however, there is little data on its use in the paediatric population. We performed a systematic review and meta-analysis on current available literature to review the safety and efficacy of NBUVB in paediatric psoriasis. METHODS: A systematic review and meta-analysis according to PRISMA guidelines. Meta-analysis of proportions was used to obtain efficacy, and meta-regression was used to explore the impact of treatment variables on efficacy. RESULTS: We identified 10 prospective and retrospective studies for inclusion. From pooled data, we determined the efficacy of NBUVB in paediatric psoriasis to be 80% (CI 70%-88%). There was a positive association between the number of treatments and efficacy of NBUVB. There was no association between the cumulative dose and efficacy. Erythema was the most commonly described side effect. There were no studies of long-term safety of NBUVB in paediatric psoriasis. Limitations included that studies had small patient numbers and were observational in nature. CONCLUSIONS: NBUVB is effective in the treatment of paediatric psoriasis with a good short-term safety profile. More studies are required to assess the influence of variables on efficacy and to elucidate the long-term safety profile of NBUVB in paediatric psoriasis.

Applying inter-rater reliability to improve consistency in classifying PhD career outcomes.

Background: There has been a groundswell of national support for transparent tracking and dissemination of PhD career outcomes. In 2017, individuals from multiple institutions and professional organizations met to create the Unified Career Outcomes Taxonomy (UCOT 2017), a three-tiered taxonomy to help institutions uniformly classify career outcomes of PhD graduates. Early adopters of UCOT 2017, noted ambiguity in some categories of the career taxonomy, raising questions about its consistent application within and across institutions. Methods: To test and evaluate the consistency of UCOT 2017, we calculated inter-rater reliability across two rounds of iterative refinement of the career taxonomy, classifying over 800 PhD alumni records via nine coders. Results: We identified areas of discordance in the taxonomy, and progressively refined UCOT 2017 and an accompanying Guidance Document to improve inter-rater reliability across all three tiers of the career taxonomy. However, differing interpretations of the classifications, especially for faculty classifications in the third tier, resulted in continued discordance among the coders. We addressed this discordance with clarifying language in the Guidance Document, and proposed the addition of a flag system for identification of the title, rank, and prefix of faculty members. This labeling system provides the additional benefit of highlighting the granularity and the intersectionality of faculty job functions, while maintaining the ability to sort by - and report data on - faculty and postdoctoral trainee roles, as is required by some national and federal reporting guidelines. We provide specific crosswalk guidance for how a user may choose to incorporate our suggestions while maintaining the ability to report in accordance with UCOT 2017. Conclusions: Our findings underscore the importance of detailed guidance documents, coder training, and periodic collaborative review of career outcomes taxonomies as PhD careers evolve in the global workforce. Implications for coder-training and use of novice coders are also discussed.

Efficient implementations of analytic energy gradient for mixed-reference spin-flip time-dependent density functional theory (MRSF-TDDFT).

Analytic energy gradients of individual singlet and triplet states with respect to nuclear coordinates are derived and implemented for the collinear mixed-reference spin-flip time-dependent density functional theory (MRSF-TDDFT), which eliminates the problematic spin-contamination of SF-TDDFT. Dimensional-transformation matrices for the singlet and triplet response spaces are introduced, simplifying the subsequent derivations. These matrices enable the general forms of MRSF-TDDFT equations to be similar to those of SF-TDDFT, suggesting that the computational overhead of singlet or triplet states for MRSF-TDDFT is nearly identical to that of SF-TDDFT. In test calculations, the new MRSF-TDDFT yields quite different optimized structures and energies as compared to SF-TDDFT. These differences turned out to mainly come from the spin-contamination of SF-TDDFT, which are largely cured by MRSF-TDDFT. In addition, it was demonstrated that the clear separation of singlet states from triplets dramatically simplifies the location of minimum energy conical intersection. As a result, it is clear that the MRSF-TDDFT has advantages over SF-TDDFT in terms of both accuracy and practicality. Therefore, it can be a preferred method, which is readily applied to other "black-box" type applications, such as the minimum-energy optimization, reaction path following, and molecular dynamics simulations.

Amino acid position 37 of HLA-DRß1 affects susceptibility to Crohn's disease in Asians.

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRß1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).

FOLD: a method to optimize power in meta-analysis of genetic association studies with overlapping subjects.

MOTIVATION: In genetic association studies, meta-analyses are widely used to increase the statistical power by aggregating information from multiple studies. In meta-analyses, participating studies often share the same individuals due to the shared use of publicly available control data or accidental recruiting of the same subjects. As such overlapping can inflate false positive rate, overlapping subjects are traditionally split in the studies prior to meta-analysis, which requires access to genotype data and is not always possible. Fortunately, recently developed meta-analysis methods can systematically account for overlapping subjects at the summary statistics level. RESULTS: We identify and report a phenomenon that these methods for overlapping subjects can yield low power. For instance, in our simulation involving a meta-analysis of five studies that share 20% of individuals, whereas the traditional splitting method achieved 80% power, none of the new methods exceeded 32% power. We found that this low power resulted from the unaccounted differences between shared and unshared individuals in terms of their contributions towards the final statistic. Here, we propose an optimal summary-statistic-based method termed as FOLD that increases the power of meta-analysis involving studies with overlapping subjects. AVAILABILITY AND IMPLEMENTATION: Our method is available at http://software.buhmhan.com/FOLD. CONTACT: mail: buhm.han@amc.seoul.kr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A Review of 52 Pedigrees with Epidermolysis Bullosa Simplex Identifying Ten Novel Mutations in KRT5 and KRT14 in Australia.

Epidermolysis bullosa simplex (EBS) is a rare heritable skin fragility disorder, most commonly caused by dominant mutations in KRT5 and KRT14. EBS shows clinical heterogeneity with localised, intermediate and generalised severe forms, which tend to correlate with the location and nature of the disease causing mutations. We therefore aimed to identify the KRT5 and KRT14 mutations in patients diagnosed with EBS in Australia, and explore in depth the genotype to the phenotype correlations in patients with novel variants. Australian patients who were diagnosed with EBS after referral to the Australian National Diagnostic Laboratory for EB were offered mutation screening in the KRT5 and KRT14 genes. From this, 32 different mutations in KRT5 and KRT14 were identified within 39 of 52 pedigrees. Ten of these mutations from 9 different pedigrees were novel, a further fatal case caused by KRT5 E477K is reported and in addition the third reported case of digenic inheritance in EBS was also observed.

Minor modifications to the phosphate groups and the C3' acyl chain length of lipid A in two Bordetella pertussis strains, BP338 and 18-323, independently affect Toll-like receptor 4 protein activation.

Lipopolysaccharides (LPS) of Bordetella pertussis are important modulators of the immune system. Interaction of the lipid A region of LPS with the Toll-like receptor 4 (TLR4) complex causes dimerization of TLR4 and activation of downstream nuclear factor κB (NFκB), which can lead to inflammation. We have previously shown that two strains of B. pertussis, BP338 (a Tohama I-derivative) and 18-323, display two differences in lipid A structure. 1) BP338 can modify the 1- and 4'-phosphates by the addition of glucosamine (GlcN), whereas 18-323 cannot, and 2) the C3' acyl chain in BP338 is 14 carbons long, but only 10 or 12 carbons long in 18-323. In addition, BP338 lipid A can activate TLR4 to a greater extent than 18-323 lipid A. Here we set out to determine the genetic reasons for the differences in these lipid A structures and the contribution of each structural difference to the ability of lipid A to activate TLR4. We show that three genes of the lipid A GlcN modification (Lgm) locus, lgmA, lgmB, and lgmC (previously locus tags BP0399-BP0397), are required for GlcN modification and a single amino acid difference in LpxA is responsible for the difference in C3' acyl chain length. Furthermore, by introducing lipid A-modifying genes into 18-323 to generate isogenic strains with varying penta-acyl lipid A structures, we determined that both modifications increase TLR4 activation, although the GlcN modification plays a dominant role. These results shed light on how TLR4 may interact with penta-acyl lipid A species.

Bordetella pertussis autotransporter Vag8 binds human C1 esterase inhibitor and confers serum resistance.

Bordetella pertussis employs numerous strategies to evade the immune system, including the ability to resist killing via complement. Previously we have shown that B. pertussis binds a complement regulatory protein, C1 esterase inhibitor (C1inh) to its surface in a Bvg-regulated manner (i.e. during its virulence phase), but the B. pertussis factor was not identified. Here we set out to identify the B. pertussis C1inh-binding factor. Using a serum overlay assay, we found that this factor migrates at approximately 100 kDa on an SDS-PAGE gel. To identify this factor, we isolated proteins of approximately 100 kDa from wild type strain BP338 and from BP347, an isogenic Bvg mutant that does not bind C1inh. Using mass spectrometry and bioinformatics, we identified the autotransporter protein Vag8 as the putative C1inh binding protein. To prove that Vag8 binds C1inh, vag8 was disrupted in two different B. pertussis strains, namely BP338 and 18-323, and the mutants were tested for their ability to bind C1inh in a surface-binding assay. Neither mutant strain was capable of binding C1inh, whereas a complemented strain successfully bound C1inh. In addition, the passenger domain of Vag8 was expressed and purified as a histidine-tagged fusion protein and tested for C1inh-binding in an ELISA assay. Whereas the purified Vag8 passenger bound C1inh, the passenger domain of BrkA (a related autotransporter protein) failed to do so. Finally, serum assays were conducted to compare wild type and vag8 mutants. We determined that vag8 mutants from both strains were more susceptible to killing compared to their isogenic wild type counterparts. In conclusion, we have discovered a novel role for the previously uncharacterized protein Vag8 in the immune evasion of B. pertussis. Vag8 binds C1inh to the surface of the bacterium and confers serum resistance.