Tag: statistics

Rheumatology (Oxford). 2022 Jun 11:keac337. doi: 10.1093/rheumatology/keac337. Online ahead of print.

ABSTRACT

OBJECTIVES: Rheumatoid Arthritis (RA) and primary Sjögren’s Syndrome (SS) carry increased atherosclerotic risk, while B cell activating factor holds a vital role in disease pathogenesis and atherosclerosis. We aimed to compare subclinical atherosclerosis profiles between the two clinical entities and define whether BAFF genetic variants alter atherosclerotic risk.

METHODS: DNA from 166 RA, 148 primary SS patients and 200 healthy controls of similar age and sex distribution was subjected to PCR-based assay for the detection of five single nucleotide polymorphisms of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569, and rs9514827). Genotype and haplotype frequencies were determined by SNPStats software and statistical analysis was performed by SPSS and Graphpad Software. Subclinical atherosclerosis was defined by the presence of carotid/femoral plaque formation and arterial wall thickening.

RESULTS: Atherosclerotic plaque formation was more frequently detected in the RA vs primary SS group (80.7% vs 62.2%, p-value <0.001), along with higher rates of family CVD history, current steroid dose, and serum inflammatory markers. The TT genotype of the rs1224141 variant was more prevalent in RA but not primary SS patients with plaque and arterial wall thickening vs their counterparts without. Regarding the rs1014569 variant, among RA patients the TT genotype increased the risk for plaque formation while in primary SS patients the AT genotype conferred increased risk. Haplotype GTTTT was protective in the RA cohort, while TATTT and TTCTT haplotypes increased susceptibility for arterial wall thickening in the primary SS cohort.

CONCLUSIONS: Increased inflammatory burden, higher steroid doses and distinct BAFF gene variations imply chronic inflammation and B cell hyperactivity as key contributors for the augmented atherosclerotic risk among autoimmune patients.

PMID:35689637 | DOI:10.1093/rheumatology/keac337

Syst Biol. 2022 Jun 11:syac040. doi: 10.1093/sysbio/syac040. Online ahead of print.

ABSTRACT

Whole-genome duplication (WGD) occurs broadly and repeatedly across the history of eukaryotes, and is recognized as a prominent evolutionary force, especially in plants. Immediately following WGD, most genes are present in two copies as paralogs. Due to this redundancy, one copy of a paralog pair commonly undergoes pseudogenization and is eventually lost. When speciation occurs shortly after WGD, however, differential loss of paralogs may lead to spurious phylogenetic inference resulting from the inclusion of pseudoorthologs-paralogous genes mistakenly identified as orthologs because they are present in single copes within each sampled species. The influence and impact of including pseudoorthologs versus true orthologs as a result of gene extinction (or incomplete laboratory sampling) is only recently gaining empirical attention in the phylogenomics community. Moreover, few studies have yet to investigate this phenomenon in an explicit coalescent framework. Here, using mathematical models, numerous simulated data sets, and two newly assembled empirical data sets, we assess the effect of pseudoorthologs on species tree estimation under varying degrees of incomplete lineage sorting (ILS) and differential gene loss scenarios following WGD. When gene loss occurs along the terminal branches of the species tree, alignment-based (BPP) and gene-tree-based (ASTRAL, MP-EST, and STAR) coalescent methods are adversely affected as the degree of ILS increases. This can be greatly improved by sampling a sufficiently large number of genes. Under the same circumstances, however, concatenation methods consistently estimate incorrect species trees as the number of genes increases. Additionally, pseudoorthologs can greatly mislead species tree inference when gene loss occurs along the internal branches of the species tree. Here, both coalescent and concatenation methods yield inconsistent results. These results underscore the importance of understanding the influence of pseudoorthologs in the phylogenomics era.

PMID:35689633 | DOI:10.1093/sysbio/syac040

Genetics. 2022 Jun 11:iyac088. doi: 10.1093/genetics/iyac088. Online ahead of print.

ABSTRACT

We develop a computationally efficient alternative, TwinEQTL, to a linear mixed-effects model (LMM) for twin genome-wide association study (GWAS) data. Instead of analyzing all twin samples together with LMM, TwinEQTL first splits twin samples into two independent groups on which multiple linear regression analysis can be validly performed separately, followed by an appropriate meta-analysis-like approach to combine the two non-independent test results. Through mathematical derivations, we prove the validity of TwinEQTL algorithm and show that the correlation between two dependent test statistics at each single-nucleotide polymorphism (SNP) are independent of its minor allele frequency (MAF). Thus the correlation is constant across all SNPs. Through simulations, we show empirically that TwinEQTL has well controlled type I error with negligible power loss compared to the gold-standard linear mixed effects models. To accommodate eQTL analysis with twin subjects, we further implement TwinEQTL into a R package with much improved computational efficiency. Our approaches provide a significant leap in terms of computing speed for GWAS and eQTL analysis with twin samples.

PMID:35689615 | DOI:10.1093/genetics/iyac088

J Surg Oncol. 2022 Jun 11. doi: 10.1002/jso.26982. Online ahead of print.

ABSTRACT

BACKGROUND: Applicability of the albumin-bilirubin (ALBI) grade in preoperative decision-making criteria based on the indocyanine green retention (ICG) test remains unclear. This study aimed to predict abnormal ICG values using standard blood tests and evaluate the impact on postoperative outcomes among patients undergoing hepatectomy for hepatocellular carcinoma (HCC).

METHODS: Data on 949 consecutive HCC patients undergoing curative-intent hepatectomy between 1996 and 2014 were retrospectively assessed. A nomogram using preoperative standard blood tests was created to predict abnormal ICGR15 (>15%).

RESULTS: Three-hundred nine patients had abnormal ICGR15. Predictors of abnormal ICGR15 included in the nomogram were: ALBI grade >1 (hazard ratio [HR]: 2.16, 95% confidence interval [CI]: 1.59-2.94), platelet count <130 000/mm³ (HR: 2.27, 95% CI: 1.68-3.08), aspartate aminotransferase >50 (IU/L) (HR: 1.90, 95% CI: 1.29-2.81), and viral hepatitis infection (HR: 1.46, 95% CI: 1.03-2.07). The nomogram named the PLT-ALBI score was discriminative [C-statistics: 0.719 (0.684-0.754)], and reliable (Hosmer-Lemeshow Chi-Square: 9.05, p = 0.338). The higher PLT-ALBI score was associated with a more frequent incidence of clinically relevant posthepatectomy liver failure and poor overall survival.

CONCLUSIONS: The PLT-ALBI score is applicable in distinguishing HCC patients with abnormal ICGR15. Patients with higher PLT-ALBI score require more careful postoperative care, despite following the ICG criteria.

PMID:35689605 | DOI:10.1002/jso.26982

Electrophoresis. 2022 Jun 11. doi: 10.1002/elps.202200075. Online ahead of print.

ABSTRACT

Affinity capillary electrophoresis was used for the simultaneous measurement of the pKa$p{K_a}$ values and of the binding constants relative to the encapsulation of naturally occurring phenolic acids (rosmarinic and caffeic acids) with cyclodextrins. A thorough study as a function of pH and temperature was coupled to a detailed statistical analysis of the resulting experimental data. A step-by-step curve fitting process was sufficient for obtaining individual binding constant for each experimental condition, but the influence of temperature remained unclear. A quantitative and qualitative gain was then obtained by supplementing this initial analysis with a global multi-parameters optimization. This lead to the estimation of both entropy and enthalpy of reaction, and to the full description of the binding reactions as a function of pH and temperature. The encapsulation was shown to be very sensitive to pH and temperature, with optimal complexation occurring at low pH and low temperature, gaining up to a factor 3 by cooling from 36°C to 15°C, and up to a factor 10 by lowering the pH from 7 to 2. This article is protected by copyright. All rights reserved.

PMID:35689604 | DOI:10.1002/elps.202200075

Schizophr Bull. 2022 Jun 11:sbac053. doi: 10.1093/schbul/sbac053. Online ahead of print.

ABSTRACT

To examine long-term effects of early intervention services (EIS) for first-episode psychosis, we compared Heinrichs-Carpenter Quality of Life (QLS) and Positive and Negative Syndrome Scale (PANSS) scores and inpatient hospitalization days over 5 years with data from the site-randomized RAISE-ETP trial that compared the EIS NAVIGATE (17 sites; 223 participants) and community care (CC) (17 sites; 181 participants). Inclusion criteria were: age 15-40 years; DSM-IV diagnoses of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, or psychotic disorder not otherwise specified; first psychotic episode; antipsychotic medication taken for ≤6 months. NAVIGATE-randomized participants could receive NAVIGATE from their study entry date until NAVIGATE ended when the last-enrolled NAVIGATE participant completed 2 years of treatment. Assessments occurred every 6 months. 61% of participants had assessments conducted ≥2 years; 31% at 5 years. Median follow-up length was CC 30 months and NAVIGATE 38 months. Primary analyses assumed data were not-missing-at-random (NMAR); sensitivity analyses assumed data were missing-at-random (MAR). MAR analyses found no significant treatment-by-time interactions for QLS or PANSS. NMAR analyses revealed that NAVIGATE was associated with a 13.14 (95%CI:6.92,19.37) unit QLS and 7.73 (95%CI:2.98,12.47) unit PANSS better improvement and 2.53 (95%CI:0.59,4.47) fewer inpatient days than CC (all comparisons significant). QLS and PANSS effect sizes were 0.856 and 0.70. NAVIGATE opportunity length (mean 33.8 (SD = 5.1) months) was not associated (P = .72) with QLS outcome; duration of untreated psychosis did not moderate (P = .32) differential QLS outcome. While conclusions are limited by the low rate of five-year follow-up, the data support long-term benefit of NAVIGATE compared to community care.

PMID:35689478 | DOI:10.1093/schbul/sbac053

Reprod Domest Anim. 2022 Jun 11. doi: 10.1111/rda.14178. Online ahead of print.

ABSTRACT

The aim of this study was to assess if vulvar morphometric changes occurring in female pigs during proestrus and estrus could be objective, accurate and predictive indicators of the onset to estrus and thus performed artificial inseminations at the most appropriate time. For that purpose, pictures of vulvas from 60 hyperprolific females (30 gilts and 30 sows) during proestrus and estrus were taken once a day. Vulva measurements (area, perimeter, length and width) on these pictures were performed using the image processing ImageJ software. Gilts and sows showed statistical differences (P<0.01) in all vulvar morphometric measurements between proestrus and estrus. Statistical differences in vulvar metrics were detected 24h before the onset to estrus, affecting all vulvar measurements in gilts, whereas only vulvar width was affected in sows. The image analysis used in this study may contribute to the development of smart technology in swine farming.

PMID:35689465 | DOI:10.1111/rda.14178

Urol J. 2022 Jun 11:7195. doi: 10.22037/uj.v19i.7195. Online ahead of print.

ABSTRACT

PURPOSE: To explore the establishment of a scoring system that can provide a reference for clinical decision making regarding the endoscopic treatment of 1-2 cm lower pole stones (LPS).

MATERIALS AND METHODS: The data of patients with renal calculi who were treated with percutaneous nephrolithotomy (PCNL) or retrograde intrarenal surgery (RIRS) in three hospitals from January 2013 to December 2017 were analyzed retrospectively. Multivariable logistic analysis was performed to determine the statistically significant indicators and regression coefficients, which were used to construct the scoring system. The stone-free rate (SFR) and postoperative complication rates of PCNL and RIRS within the two fractional segments of the scoring system were compared to select the optimal procedures.

RESULTS: A total of 137 patients in the PCNL group and 152 patients in the RIRS group were included in this study. Five factors were found to be most predictive of endoscopic treatment choice: stone number, stone diameter, infundibulopelvic angle (IPA), infundibular length (IL), and infundibular width (IW), yielding a total score ranging from 0-5. In the 0-2 segments, the RIRS group had better outcomes than the PCNL group in terms of the postoperative complication rates (6.8% versus 18.0%, P = .026). In segments 3-5, the SFR of the PCNL group was significantly higher than that of the RIRS group (88.5% versus 70.6%, P = .017).

CONCLUSION: Our scoring system was based on the patient’s preoperative imaging examination to measure the stone number, stone diameter, IPA, IL and IW. RIRS was recommended at 0-2 segments, and PCNL was recommended at 3-5 segments. This new scoring system is expected to provide guidance for urologists to make endoscopic treatment decisions for 1-2 cm LPS.

PMID:35689463 | DOI:10.22037/uj.v19i.7195

J Bone Miner Res. 2022 Jun 11. doi: 10.1002/jbmr.4632. Online ahead of print.

ABSTRACT

New therapies may help to prevent osteoporotic fractures other than through increasing bone mineral density (BMD). Since fracture risk has an important genetic component, we aim to identify loci increasing fracture risk which do not decrease BMD, using a recently-proposed structural equation model adapted to remove genetic influences of BMD on fracture risk. We used summary statistics of the largest genome-wide association studies for BMD and for fracture in these analyses. We next estimated the genetic correlation between the non-BMD or BMD-related genetic effects and other clinical risk factors for fracture. Lastly, based on White British participants in the UK Biobank, we conducted genetic risk score analyses to assess whether the aggregated genetic effects conferred increased major osteoporotic fracture risk. We found that only three loci affecting fracture risk exhibited genetic effects not mediated by BMD: SOST, CPED1-WNT16, and RSPO3, while these three loci simultaneously conferred BMD-related effects. No strong genetic associations between non-BMD or BMD-related effects and 16 clinical risk factors were observed. However, non-BMD effects might be genetic correlated with hip bone size. In the UK Biobank, a one standard deviation increase in the non-BMD genetic risk score conferred an odds ratio of 1.17 of incident major osteoporotic fracture, compared to 1.29 for a BMD-related genetic risk score. Our study suggests that the vast majority of common genetic predisposition towards fracture risk acts upon BMD. While non-BMD genetic effects may exist, they are not strongly correlated with most traditional clinical risk factors. Risk loci harboring non-BMD genetic effects may influence other perspectives of bone quality, or confer effects that existing genome-wide association studies fail to capture, but they demonstrate weaker impact on fracture risk than BMD-related genetic effects. These findings suggest that most successful drug development programs for osteoporosis should focus on pathways identified through BMD-associated loci. This article is protected by copyright. All rights reserved.

PMID:35689460 | DOI:10.1002/jbmr.4632

Hum Reprod. 2022 Jun 11:deac136. doi: 10.1093/humrep/deac136. Online ahead of print.

ABSTRACT

STUDY QUESTION: Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different?

SUMMARY ANSWER: Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified.

WHAT IS KNOWN ALREADY: Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive.

STUDY DESIGN, SIZE, DURATION: In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021.

PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche.

MAIN RESULTS AND THE ROLE OF CHANCE: In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P < 10-10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P < 10-10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche.

LIMITATIONS, REASONS FOR CAUTION: A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue.

WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease.

STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests.

TRIAL REGISTRATION NUMBER: N/A.

PMID:35689443 | DOI:10.1093/humrep/deac136