Case-control Setting Research Articles

Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score.

Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified. To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers. We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS. After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and + 10 years of age; P = 0.008). Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. © 2020 International Parkinson and Movement Disorder Society.

Deep learning modeling using normal mammograms for predicting breast cancer risk.

Toinvestigate two deep learning-based modeling schemes for predicting short-term risk of developing breast cancer using prior normal screening digital mammograms in a case-control setting. We conducted a retrospective Institutional Review Board-approved study on a case-control cohort of 226 patients (including 113 women diagnosed with breast cancer and 113 controls) who underwent general population breast cancer screening. For each patient, a prior normal (i.e., with negative or benign findings) digital mammogram examination [including mediolateral oblique (MLO) view and craniocaudal (CC) view two images] was collected. Thus, a total of 452 normal images (226 MLO view images and 226 CC view images) of this case-control cohort were analyzed to predict the outcome, i.e., developing breast cancer (cancer cases) or remaining breast cancer-free (controls) within the follow-up period. We implemented an end-to-end deep learning model and a GoogLeNet-LDA model and compared their effects in several experimental settings using two mammographic view images and inputting two different subregions of the images to the models. The proposed models were also compared to logistic regression modeling of mammographic breast density. Area under the receiver operating characteristic curve (AUC) was used as the model performance metric. The highest AUC was 0.73 [95% Confidence Interval (CI): 0.68-0.78; GoogLeNet-LDA model on CC view] when using the whole-breast and was 0.72 (95% CI: 0.67-0.76; GoogLeNet-LDA model on MLO+CC view) when using the dense tissue, respectively, as the model input. The GoogleNet-LDA model significantly (all P<0.05) outperformed the end-to-end GoogLeNet model in all experiments. CC view was consistently more predictive than MLO view in both deep learning models, regardless of the input subregions. Both models exhibited superior performance than the percent breast density (AUC=0.54; 95% CI: 0.49-0.59). The proposed deep learning modeling approach can predict short-term breast cancer risk using normal screening mammogram images. Larger studies are needed to further reveal the promise of deep learning in enhancing imaging-based breast cancer risk assessment.

Body mass index and risk of breast cancer molecular subtypes in Korean women: a case-control study.

Our main objective of this research was to analyze the effect of BMI on breast cancer risk according to various subtypes of breast cancer stratified with menopausal status. By using a case-control study setting, we recruited a total of 16,190 female breast cancer patients aged between 35 and 80years from 2003 to 2010. These breast cancer patients were then individually matched by age to control female group (1:2 ratios of cases and controls). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via multivariable logistic regression by setting normal BMI range (18.5-22.9) as the reference group. In premenopausal women, the risk of breast cancer of triple-negative subtype increased (OR 1.60, 95% CI 1.27-2.02) in obese II (BMI ≥ 30) women and in underweight women, it was Luminal A (OR 1.24, 95% CI 1.06-1.45) and HER2 express subtype (OR 1.43, 95% CI 1.26-1.62) that showed increased risk of breast cancer. In postmenopausal women, Luminal A (OR 2.35, 95% CI 2.01-2.75), Luminal B HER2 negative (OR 1.81, 95% CI 1.46-2.25) and triple-negative subtype (OR 2.25, 95% CI 1.85-2.72) showed higher risk of breast cancer in obese II women. Our findings suggest that the effect of BMI on breast cancer differs according to various subtypes and hormone receptors and to menopausal status.

Plasma Metabolic Signature and Abnormalities in HIV-Infected Individuals on Long-Term Successful Antiretroviral Therapy.

Targeted metabolomics studies reported metabolic abnormalities in both treated and untreated people living with human immunodeficiency virus (HIV) (PLHIV). The present study aimed to understand the plasma metabolomic changes and predicted the risk of accelerated aging in PLHIV on long-term suppressive antiretroviral therapy (ART) in a case-control study setting and its association with the plasma proteomics biomarkers of inflammation and neurological defects. Plasma samples were obtained from PLHIV on successful long-term ART for more than five years (n = 22) and matched HIV-negative healthy individuals (n = 22, HC herein). Untargeted metabolite profiling was carried out using ultra-high-performance liquid chromatography/mass spectrometry/mass spectrometry (UHPLC/MS/MS). Plasma proteomics profiling was performed using proximity extension assay targeting 184 plasma proteins. A total of 250 metabolites differed significantly (p < 0.05, q < 0.1) between PLHIV and HC. Plasma levels of several essential amino acids except for histidine, branched-chain amino acids, and aromatic amino acids (phenylalanine, tyrosine, tryptophan) were significantly lower in PLHIV compared to HC. Machine-learning prediction of metabolite changes indicated a higher risk of inflammatory and neurological diseases in PLHIV. Metabolic abnormalities were observed in amino-acid levels, energetics, and phospholipids and complex lipids, which may reflect known differences in lipoprotein levels in PLHIV that can resemble metabolic syndrome (MetS).

Observational cross-sectional study on Symptoms Associated to Moisture DAmage at Workplace: the SAMDAW study protocol

IntroductionMoisture damage (MD) exposure at work has been shown to increase the risk of new onset asthma and exacerbation of asthma. However, most of the studies in this field have...

Urinary TERT promoter mutations as non-invasive biomarkers for the comprehensive detection of urothelial cancer

BackgroundRecurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring. However, the possibility of detecting these mutations in cell-free circulating DNA (cfDNA) in blood and urine, or DNA from urinary exfoliated cells (cellDNA) with a single-gene sensitive assay has never been tested in a case-control setting. MethodsWe developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations. We tested 93 primary and recurrent UC cases and 94 controls recruited in France (blood, urine samples and tumours for the cases), and 50 primary UC cases and 50 controls recruited in Portugal (urinary exfoliated cell samples). We compared our assay with urine cytology. FindingsIn the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87·1%; 95% CI 78·6–93·2), and five controls (Specificity 94·7%; 95%CI 88·0–98·3), with 98·6% (95% CI 92·5–99·96) concordance in matched tumours. Detection rate in plasma cfDNA among cases was 7·1%. The UroMuTERT sensitivity was (i) highest for urinary cfDNA and cellDNA combined, (ii) consistent across primary and recurrent cases, tumour stages and grades, (iii) higher for low-risk non-muscle invasive UC (86·1%) than urine cytology (23·0%) (P < 0·0001) and (iv) 93·9% when combined with cytology. In the Portuguese series – the sensitivity and specificity for detection of UC with urinary cellDNA was 68·0% (95% CI 53·3–80·5) and 98·0% (95% CI 89·3–100·0). InterpretationTERT promoter mutations detected by the UroMuTERT assay in urinary DNA (cfDNA or cellDNA) show excellent sensitivity and specificity for the detection of UC, significantly outperforming that of urine cytology notably for detection of low-grade early stages UC. FundFrench Cancer League; French Foster Research in Molecular Biology and European Commission FP7 Marie Curie COFUND.

Association of the MUTYH Gln324His (CAG/CAC) variant with cervical carcinoma and HR-HPV infection in a Chinese population.

This study was performed to investigate the relationship between the MUTYH Gln324His (CAG/CAC) genotype and risk of cervical squamous cell carcinoma (CSCC) in a case-control setting. Mismatch amplification-polymerase chain reaction (MA-PCR) was applied to detect the polymorphism in 400 CSCC, 400 CIN III and 1200 control participants. The homozygous His324His (CAC/CAC) genotype of MUTYH was associated with significantly increased risk of CIN III (OR = 1.94) and CSCC (OR = 3.83). Increased risk of CIN III (OR = 1.34) and CSCC (OR = 1.97) was additionally observed with the heterozygous CAG/CAC genotype. Overall, individuals in both CAC/CAC and CAG/CAC genotype groups were at higher risk of cervical carcinoma (CINIII (OR = 1.46) and CSCC (OR = 2.34)). Within the HR-HPV infection-positive group, CAC/CAC and CAG/CAC genotypes were significantly enriched in relation to CIN III and CSCC. Moreover, we observed a positive correlation between the proportion of homozygous CAC/CAC MUTYH genotype and malignant prognostic factors of CSCC, such as cell differentiation grade and lymph node metastasis. These findings clearly highlight associations between the MUTYH Gln324His (CAG/CAC) polymorphism and susceptibility to CSCC, HR-HPV infection and specific prognostic factors, supporting the utility of this variant as an early indicator for patients at high risk of cervical carcinoma.

Effects of Omitting Non-confounding Predictors From General Relative-Risk Models for Binary Outcomes.

BackgroundThe effects, in terms of bias and precision, of omitting non-confounding predictive covariates from generalized linear models have been well studied, and it is known that such omission results in attenuation bias but increased precision with logistic regression. However, many epidemiologic risk analyses utilize alternative models that are not based on a linear predictor, and the effect of omitting non-confounding predictive covariates from such models has not been characterized.MethodsWe employed simulation to study the effects on risk estimation of omitting non-confounding predictive covariates from an excess relative risk (ERR) model and a general additive-multiplicative relative-risk mixture model for binary outcome data in a case-control setting. We also compared the results to the effects with ordinary logistic regression.ResultsFor these commonly employed alternative relative-risk models, the bias was similar to that with logistic regression when the risk was small. More generally, the bias and standard error of the risk-parameter estimates demonstrated patterns that are similar to those with logistic regression, but with greater magnitude depending on the true value of the risk. The magnitude of bias and standard error had little relation to study size or underlying disease prevalence.ConclusionsPrior conclusions regarding omitted covariates in logistic regression models can be qualitatively applied to the ERR and the general additive-multiplicative relative-risk mixture model without substantial change. Quantitatively, however, these alternative models may have slightly greater omitted-covariate bias, depending on the magnitude of the true risk being estimated.

Bayesian variable selection logistic regression with paired proteomic measurements.

We explore the problem of variable selection in a case‐control setting with mass spectrometry proteomic data consisting of paired measurements. Each pair corresponds to a distinct isotope cluster and each component within pair represents a summary of isotopic expression based on either the intensity or the shape of the cluster. Our objective is to identify a collection of isotope clusters associated with the disease outcome and at the same time assess the predictive added‐value of shape beyond intensity while maintaining predictive performance. We propose a Bayesian model that exploits the paired structure of our data and utilizes prior information on the relative predictive power of each source by introducing multiple layers of selection. This allows us to make simultaneous inference on which are the most informative pairs and for which—and to what extent—shape has a complementary value in separating the two groups. We evaluate the Bayesian model on pancreatic cancer data. Results from the fitted model show that most predictive potential is achieved with a subset of just six (out of 1289) pairs while the contribution of the intensity components is much higher than the shape components. To demonstrate how the method behaves under a controlled setting we consider a simulation study. Results from this study indicate that the proposed approach can successfully select the truly predictive pairs and accurately estimate the effects of both components although, in some cases, the model tends to overestimate the inclusion probability of the second component.

Identifying MRI-detected inflammatory features specific for rheumatoid arthritis: two-fold feature reduction maintains predictive accuracy in clinically suspect arthralgia patients

ObjectiveMRI-detected inflammation is considered of diagnostic value for rheumatoid arthritis (RA), but its evaluation involves a time-consuming scoring of 61 joint-level features. It is not clear, however, which of these features are specific for RA and whether evaluating a subset of specific features is sufficient to differentiate RA patients. This study aimed to identify a subset of RA-specific features in a case–control setting and validate them in a longitudinal cohort of arthralgia patients. MethodsThe difference in frequency of MRI-detected inflammation (bone marrow edema, synovitis, and tenosynovitis) between 199 RA patients and 193 controls was studied in 61 features across the wrist, metacarpophalangeal, and metatarsophalangeal joints. A subset of RA-specific features was obtained by applying a cutoff on the frequency difference while maximizing discriminative performance. For validation, this subset was used to predict arthritis development in 225 clinically suspect arthralgia (CSA) patients. Diagnostic performance was compared to a reference method that uses the complete set of 61 features normalized for inflammation levels in age-matched controls. ResultsSubset of 30 features, mainly (teno)synovitis, was obtained from the case–control setting. Validation in CSA patients yielded an area of 0.69 (95% CI: 0.59–0.78) under the ROC curve and a positive predictive value (PPV) of 31%, compared to 0.68 (95% CI: 0.60–0.77) and 29% PPV of the reference method with 61 features. ConclusionSubset of 30 MRI-detected inflammatory features, dominated by (teno)synovitis, offers a considerable reduction of scoring efforts without compromising accuracy for prediction of arthritis development in CSA patients.

Observational Studies in Bariatric Surgery

: In medical literature, studies are divided into two categories; experimental and observational settings. Experimental studies, entitled randomized controlled trials could test the relationship between exposure and outcome experimentally via control group and random allocation. Observational settings include either analytical or descriptive studies. Descriptive studies consist of case reports and case series that are helpful in present the experience of a case or a series of cases with similar diagnoses in detail which results in hypothesis generation. Cross-sectional studies, as analytical designs, are not capable to survey the temporality of exposure and outcome as simultaneously exposure and outcome status are measured. In case-control studies, subjects follow back from outcome to exposure. The rare diseases are recommended to study using case-control setting to save expenses and time. Both exposure measurement and patient selection is before disease detection in cohort studies. Therefore, they are inefficient for rare diseases or diseases with long latency. Cohort studies are time consuming with high cost and loss to follow-up. This paper elaborately reviews the features, advantages, and disadvantages of different types of observational and experimental studies.

Perceived Physical Strain at Work and Incidence of Prostate Cancer – a Case-Control Study in Sweden and Finland

The evidence that prostate cancer is associated to physical inactivity is inconsistent. We studied the association of perceived physical workload (PPWL) at work and incidence of prostate cancer in a case-control setting. We used data from the Nordic Occupational Cancer study from Finland and Sweden. Five population controls were selected for each prostate cancer patient, matched on age and country. We had 239,835 cases and 1,199,175 controls in our study. For each case and control we estimated cumulative PPWL based on probability, level and duration of PPWL using the NOCCA Job Exposure Matrix. We then stratified individuals as having no exposure (reference category), low physical activity (below 50th percentile of the exposed), moderate exposure (50th-90th percentile) and high exposure (90th percentile and higher). The hazard ratios for prostate cancer from the lowest to highest cumulative PPWL levels were 0.90 (95% confidence interval 0.89-0.91), 0.88 (0.87-0.89) and 0.93 (0.92-0.95). There was no statistically significant dose response effect of PPWL on prostate cancer incidence. Inclusion of socioeconomic status in the model did not substantially change the result. The results were similar before Prostate Specific Antigen (PSA) testing and during the years of PSA testing in these countries. In summary, individuals with physical strain at work had a lower risk of invasive prostate cancer as compared to individuals without physical strain at work.

Persistent Oral Human Papillomavirus (HPV) Infection is Associated with Low Salivary Levels of Matrix Metalloproteinase 8 (MMP-8)

BackgroundA persistent human papillomavirus (HPV) infection is a prerequisite for a HPV related cancer to develop. Asymptomatic, persistent HPV infections are not only found in genital tract, but also on oral mucosa. Oral HPV persistence may be associated with behavioural factors, but data on the role of innate immunity in oral HPV infections are still limited. ObjectivesSalivary concentrations of matrix metalloproteinases MMP-8 and MMP-9, tissue inhibitor of MMPs (TIMP-1), myeloperoxidase, and serum concentrations of MMP-8 were analysed in women with a persistent oral HPV infection and, as a control, in women who remained HPV DNA-negative during a 6-year follow-up. The effects of smoking, lactation and alcohol use on the salivary and serum parameters were assessed, too. Study designA nested case-control setting was used to select a subgroup of 57 women with a persistent oral HPV infection and 102 controls from the Finnish Family HPV Study. ResultsThe salivary MMP-8/TIMP-1 molar ratio was lower in HPV DNA-positive women than in controls (p=0.036). The difference was more pronounced in non-smoking women, in this group also the salivary MMP-8 levels differed (p=0.047). There was a correlation between the salivary concentrations of myeloperoxidase and MMP-8 (r=0.567, p<0.001) or MMP-9 (r=0.234, p=003), but no correlation between salivary and serum MMP-8 levels. The MMP-9 concentration and the MMP-9/TIMP-1 molar ratio were significantly lower in smokers than in non-smokers (p=0.020 and p=0.003, respectively). ConclusionsPersistent oral HPV infection was associated with a low salivary MMP-8 concentration indicating eventually a failure in oral anti-inflammatory defence.

Abstract 2274: Extreme telomere length was associated with gastric adenocarcinoma risk: The Singapore Chinese Health Study

Abstract Background: Evidence regarding extreme telomere length and increased gastric cancer risk has been limited in retrospective case-control study setting which was potentially subjected to selection bias and reverse causality. We conducted a prospective analysis in an Eastern Asian population to examine the hypothesis that extreme telomere length is associated with increased risk of gastric adenocarcinoma. Methods: Among 63,257 participants of the Singapore Chinese Health Study, a population-based prospective cohort of Chinese men and women aged 45-74 years recruited between 1993 and 1998, 28,219 provided baseline blood samples. We used quantitative polymerase chain reaction (PCR) method to quantify relative telomere length determined by the ratio of telomere repeat copy number (T) to single-copy gene for albumin (S) (i.e., TSR) on all subjects. The present analysis included 24,846 subjects with valid TSR values after excluding samples with insufficient DNA (n = 1,908) and/or patients with prevalent cancer at baseline blood draw (n = 1,465). As of December 31, 2014, 191 study participants who were free of cancer developed gastric adenocarcinoma. The information on demographic and lifestyle characteristics was collected using structured questionnaires at baseline and two follow-up interviews. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and the corresponding 95% confidence interval (CI) of developing gastric adenocarcinoma for different levels of decile TSR. Restricted cubic spline (RCS) analysis was applied to examine the nonlinear relationship between TSR level and gastric adenocarcinoma risk. Results: The RCS analysis revealed a U-shaped relationship between TSR and gastric adenocarcinoma risk (p-value for non-linear association=0.009). Compared with the 4th decile, HR (95% CI) for the lowest and highest deciles of TSR 2.27 (1.17-4.40) and 1.98 (0.95-4.13), respectively after adjusting for age, sex, education, interview year, dialect group and smoking status. Conclusions: This was the first prospective analysis of TSR and risk of developing gastric adenocarcinoma in a general population. The study demonstrates both extreme short and long telomere length to be associated with significantly increased risk of gastric adenocarcinoma. These results suggest a complex relationship between telomere length and gastric cancer risk. Citation Format: Zhensheng Wang, Woon-Puay Koh, Aizhen Jin, Renwei Wang, Jian-Min Yuan. Extreme telomere length was associated with gastric adenocarcinoma risk: The Singapore Chinese Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2274. doi:10.1158/1538-7445.AM2017-2274

Investigating Types and Frequency of Vascular Findings in Pulmonary CT Angiography of Baker females with Pulmonary Complaints in Comparison with Chronic Obstructive Pulmonary Disease

Still in many places all over the world including East Azerbaijan Province and particularly in rural areas, women use traditional methods such as using oven and organic fuels (wood, turd) to bake bread. It has been shown that the smoke organic fuels in places with inadequate ventilation for a long term may cause a range of problems in the respiratory system. CT angiography is a good and less invasive method in evaluating pulmonary vascular system. This study tried to compare CT angiography findings in the lungs of bread-cooking women with respiratory complaints and females with COPD and no history of bread cooking. In this case-control setting, 36 patients in the bread-cooking group (case) and 36 patients with COPD in the control group underwent lung CT angiography. Pathologic findings including dilation of the bronchial arteries, hyper vascularization of the bronchial arteries, changes in pulmonary trunk diameter, silent embolism and any other abnormal changes were documented and compared between the two groups. The mean duration of bread-cooking was 4.78±3.17 years (2-12). Abnormal vascular findings in lung CT angiographies of the bread-cooking women with respiratory complaints were dilation of the bronchial arteries (22.2%), hyper vascularization of the bronchial arteries (8.3%), silent embolism (11.1%) and parenchymal emphysematous changes (13.9%). They were documented in the COPD group in 36.1%, 27.8%, 27.8% and 3.33% of the patients, respectively. Accordingly, the frequency of hyper vascularization of the bronchial arteries and parenchymal emphysematous changes was significantly higher in the COPD group than in the bread-cooking women. In contrast, the mean diameter of the pulmonary trunk was significantly higher in the bread-cooking group (3.32 vs. 3.17 cm). Abnormal findings in lung CT angiography of bread-cooking women with respiratory symptoms are frequent and in some cases, they are different from findings in the lungs of women with COPD and no previous history of bread-cooking.

FAS c.-671A>G polymorphism and cervical cancer risk: a case–control study and meta-analysis

This study aimed to investigate the association between FAS c.-671A>G polymorphism and cervical cancer risk in a case-control setting, followed by a meta-analysis of the published literatures. The case-control study involved genotyping of the polymorphism in 185 histopathologically confirmed cervical cancer patients and 209 cancer-free female controls utilizing PCR-RFLP technique, followed by logistic regression analyses. Meta-analysis was then conducted under homozygous, heterozygous, dominant, recessive and allele contrast models to combine data from 12 studies which consisted of 2798 cases and 3039 controls. Our case-control analysis revealed a significant association of the variant allele (G) and the homozygous variant genotype (GG) of the FAS polymorphism with an increased risk of cervical cancer. Subgroup analysis by ethnicity further confirmed the risk association in Malays (P < 0.05), but not among non-Malays (P > 0.05). However, results of meta-analysis suggested a lack of association between the polymorphism and cervical cancer risk in all the five genetic models analyzed. In conclusion, while the FAS c.-671A>G polymorphism may serve as a biomarker for cervical cancer risk prediction among the Malays, there is a limited usability of the polymorphism as a cervical cancer risk biomarker in other populations.

Applicability of automatic spectral domain optical coherence tomography for glaucoma mass screening.

PurposeTo perform a preliminary evaluation of the applicability of automatic spectral domain optical coherence tomography (ASD-OCT) for glaucoma mass screening in a population-based setting.MethodsInformation using ASD-OCT (thicknesses of the macular retinal nerve fiber layer [mRNFL], disc retinal nerve fiber layer [dRNFL], ganglion cell layer [GCL] + inner plexiform layer [IPL]; GCL+, and ganglion cell complex [GCL + IPL + RNFL; GCL++]) was obtained from 245 eyes of 123 glaucomatous subjects and 1,454 eyes of 727 normal subjects. For all four measurements, each grid was scored as follows: 2= within 95% of the normal database; 1= within 5%; and 0= within 1%. The sums of each grid (mRNFLs, dRNFLs, GCL+s, and GCL++s) were used as indicators. The effectiveness was estimated by the area under the receiver operating characteristic curve (AUC-ROC). The appropriate algorithm was then applied to 10,145 eyes of 5,088 subjects from the general population (mean age: 50.1±10.3 years).ResultsAUC-ROC of mRNFLs, dRNFLs, GCL+s, and GCL++s was 0.927 (95% confidence interval [CI] =0.903–0.950), 0.919 (95% CI =0.899–0.940), 0.972 (95% CI =0.958–0.986), and 0.972 (95% CI =0.957–0.986), respectively. The discriminant analysis demonstrated that the canonical correlation coefficients of mRNFLs, dRNFLs, GCL+s, and dGCL++s were 0.07, 0.255, 0.661, and 0.207, respectively. AUC-ROC of the discriminant value was 0.971 (95% CI =0.956–0.986). The sensitivity/specificity using GCL+s (cutoff =160) was 81.6%/99.9%. This algorithm was applied to the general population, and 1,658 eyes (16.3%) were found to be positive for glaucoma.ConclusionIn the case–control setting, ASD-OCT showed a relatively high performance, and the thickness of the GCL + IPL was the best predictor. However, further prospective studies are needed, in which the results of this study are compared to the general population, because the false-positive rate of glaucoma seems to be high.

Association of non-synonymous variants in WIPF3 and LIPA genes with abdominal aortic aneurysm: an autopsy study.

BackgroundAbdominal aortic aneurysm (AAA) is a multifactorial disease with strong genetic components. Various genetic loci have been associated with clinical AAA, but few studies have investigated pathological AAA, an intermediate phenotype of the disease.MethodsWe examined 2263 consecutive autopsies of older Japanese subjects from a study on geriatric diseases in Japanese individuals (The JG-SNP study). The presence of AAA was determined with a pathological diagnosis during autopsy. Single nucleotide variants (SNVs) associated with AAA were determined with an Illumina HumanExome Beadchip array. Logistic regression analyses were performed to determine genetic associations. Age, gender, and other risk factors of AAA were analyzed as covariates.Results118 subjects with AAA and 2145 subjects without AAA were analyzed in a case-control setting. No variants reached significance after applying the Bonferroni correction (P < 2.05×10−6). The strongest associations were found with rs3750092 (p.E321G, OR: 0.36, 95% CI: 0.24–0.56, P = 6.09 × 10−6), a variant in the WAS/WASL interacting protein family 3 (WIPF3), and with rs1051338 (p.T16P, OR: 2.50, 95% CI: 1.70–3.66, P = 2.79 × 10−6) and rs2246942 (intronic, OR: 2.32, 95% CI: 1.58–3.41, P = 1.61 × 10−5), variants in the lysosomal acid lipase A (LIPA). LIPA is essential for macrophage cholesterol metabolism. Immunohistological analyses of WIPF3 protein in AAA samples from three subjects revealed that WIPF3 was expressed in macrophages of atheromatous plaques.ConclusionsThis study suggests that WIPF3 and LIPA, both of which are expressed in the macrophages are involved in pathological AAA. These results should be regarded as hypothesis-generating; thus, replication study is warranted.

Detection of Human Papillomavirus in Korean Breast Cancer Patients by Real-Time Polymerase Chain Reaction and Meta-Analysis of Human Papillomavirus and Breast Cancer.

BackgroundHuman papillomavirus (HPV) is a well-established oncogenic virus of cervical, anogenital, and oropharyngeal cancer. Various subtypes of HPV have been detected in 0% to 60% of breast cancers. The roles of HPV in the carcinogenesis of breast cancer remain controversial. This study was performed to determine the prevalence of HPV-positive breast cancer in Korean patients and to evaluate the possibility of carcinogenic effect of HPV on breast.MethodsMeta-analysis was performed in 22 case-control studies for HPV infection in breast cancer. A total of 123 breast cancers, nine intraductal papillomas and 13 nipple tissues of patients with proven cervical HPV infection were tested by real-time polymerase chain reaction to detect 28 subtypes of HPV. Breast cancers were composed of 106 formalin-fixed and paraffin embedded (FFPE) breast cancer samples and 17 touch imprint cytology samples of breast cancers.ResultsThe overall odds ratio between breast cancer and HPV infection was 5.43 (95% confidence interval, 3.24 to 9.12) with I² = 34.5% in meta-analysis of published studies with case-control setting and it was statistically significant. HPV was detected in 22 cases of breast cancers (17.9%) and two cases of intaductal papillomas (22.2%). However, these cases had weak positivity.ConclusionsThese results failed to serve as significant evidence to support the relationship between HPV and breast cancer. Further study with larger epidemiologic population is merited to determine the relationship between HPV and breast cancer.

Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort.

We aimed to determine the prevalence of melanocortin-4 receptor (MC4R) variants in a large German cohort of children with obesity in a pediatric outpatient clinic and to ascertain whether there is a specific phenotype associated with loss-of-function variants as previously reported. Eight hundred and ninety-nine patients from our pediatric obesity clinic were screened for MC4R variants by DNA sequencing after PCR amplification. Retrospective statistical analysis of anthropometric and metabolic characteristics was performed, comparing patients with and without MC4R variants across the entire cohort (n=586) as well as in case-control analysis using patients with common sequence MC4R individually matched for age, sex and body mass index standard deviation score (SDS) (n=11 case-control pairs). We identified heterozygous variants within the coding region of the MC4R gene in n=22 (2.45%) patients. Fourteen (1.56%) had a variant that impaired receptor function. One new frameshift (p.F152Sfs), an yet unpublished nonsense mutation (p.Q156X) and one nonsynonymous variation (p.V65E) described in the Mouse Genome Database were detected. Across the whole cohort, at all ages, mean height SDS in subjects with impaired receptor function was higher than in patients with common sequence MC4R. In matched individuals, this trend persisted (8 of the 11 pairs) within the case-control setting. No differences were found regarding metabolic characteristics. The observed prevalence of mutations causing impaired receptor function in this large cohort is comparable to other pediatric cohorts. MC4R deficiency tends to lead to a taller stature, confirming previous clinical reports. The association of MC4R mutations with a distinct phenotype concerning metabolic characteristics remains questionable.