Abstract
Motivation
The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are ...still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions.
Results
We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies.
Availability and implementation
The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY_Software/.
Supplementary information
Supplementary data are available at Bioinformatics online.
Testing SNP-SNP interactions is considered as a key for overcoming bottlenecks of genetic association studies. However, related statistical methods for testing SNP-SNP interactions are ...underdeveloped.
We propose the SNP Interaction Pattern Identifier (SIPI), which tests 45 biologically meaningful interaction patterns for a binary outcome. SIPI takes non-hierarchical models, inheritance modes and mode coding direction into consideration. The simulation results show that SIPI has higher power than MDR (Multifactor Dimensionality Reduction), AA_Full, Geno_Full (full interaction model with additive or genotypic mode) and SNPassoc in detecting interactions. Applying SIPI to the prostate cancer PRACTICAL consortium data with approximately 21 000 patients, the four SNP pairs in EGFR-EGFR , EGFR-MMP16 and EGFR-CSF1 were found to be associated with prostate cancer aggressiveness with the exact or similar pattern in the discovery and validation sets. A similar match for external validation of SNP-SNP interaction studies is suggested. We demonstrated that SIPI not only searches for more meaningful interaction patterns but can also overcome the unstable nature of interaction patterns.
The SIPI software is freely available at http://publichealth.lsuhsc.edu/LinSoftware/ .
hlin1@lsuhsc.edu.
Supplementary data are available at Bioinformatics online.
Abstract Objectives The aim of this study was to compare the effects of three different surface treatments in enhancing porcelain zirconia bonding. Methods Totally, 160 densely sintered zirconia ...specimens were prepared and randomly divided into four study groups: control (no treatment, Group C), sandblasting (Group S), sandblasting followed by regeneration firing (Group SH), and laser irradiation (pulse mode) on a CO2 laser system (Group L). After surface treatment, porcelain powders were veneered on zirconia surface. Half of the specimens in each group were evaluated without aging (initial shear bond strength – initial SBS), and the other half was tested after being stored in water for one month (aging SBS). X-ray diffractometry (XRD) was used to observe any crystallographic transformation at zirconia surface. Results were statistically analyzed using analysis of variance (ANOVA) and Turkey test (=0.05). Results The initial average SBS values of Group S, Group SH, and Group L were 31.3 ± 5.7 MPa, 29.2 ± 7.0 MPa and 32.1 ± 7.5 MPa, respectively. The differences among these three groups were not significant. The control group had significantly lower value, 24.8 ± 6.7 MPa, than those of Group S and Group L. Furthermore, there was no significant difference between initial and aging values in each group. XRD analysis showed that sandblasting caused tetragonal to monoclinic phase transformation. Regeneration firing reversed such a transformation. However, crystallographic transformation could not be detected in laser treated specimens. Significance Both sandblasting and laser irradiation increased porcelain zirconia bond strength. The presented new modified laser pre-treatment might be an alternative way to sandblasting for improving zirconia/porcelain integration.
Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.
Patients were enrolled after ...they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.
A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 95% confidence interval {CI}, 0.17 to 0.48; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 95% CI, 0.59 to 0.85; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 95% CI, 1.00 to 1.85; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.
Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.).
The perioperative period can be a critical period with long-term implications on cancer-related outcomes. In this study, we evaluate the influence of regional anesthesia on cancer-specific outcomes ...in a radical cystectomy (RC) cohort of patients.
We performed a retrospective analysis of patients with clinically-nonmetastatic urothelial carcinoma of the bladder who underwent RC at our institution from 2008 to 2012. Patients were retrospectively registered and stratified based on two anesthetic techniques: perioperative epidural analgesia with general anesthesia (epidural) versus general anesthesia alone (GA). Epidural patients received a sufentanil-based regimen (median intraoperative sufentanil dose 50 mcg (45,85). Propensity-score was used to make 1:1 case-control matching. Cumulative risk of recurrence with competing risks was calculated based on anesthetic technique. Kaplan-Meier curves were used to compare recurrence-free (RFS) and cancer-specific survival (CSS). Univariable and multivariable analyses were performed with Cox proportional hazard regression models for RFS and CSS.
Only patients with complete data on anesthetic technique were included. Out of 439 patients, 215-pair samples with complete follow-up were included in the analysis. Median follow-up was 41.4 months (range: 0.20-101). Patients with epidurals received higher median total intravenous morphine equivalents (ivMEQ) versus those in the GA group (75 (11-235) vs. 50 ivMEQ (7-277), p < 0.0001). Cumulative risk of recurrence at two years was 25.2% (19.6, 31.2) for epidural patients vs. 20.0% (15.0, 25.7) for GA patients (Gray test p = 0.0508). Epidural analgesic technique was a significant predictor of worse RFS (adjusted HR = 1.67, 1.14-2.45; p = 0.009) and CSS (HR = 1.53, 1.04-2.25; p = 0.030) on multivariable analyses.
Epidural anesthesia using sufentanil was associated with worse recurrence and disease-free survival in bladder cancer patients treated with surgery. This may be due use of epidural sufentanil or due to the increased total morphine equivalents patient received as a consequence of this drug.
Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to ...risk classify African American men is thus far lacking in a prospective setting.
This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score.
The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk RR = 2.23, 95% confidence interval CI = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes.
Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.
Background
Non–vitamin K antagonist oral anticoagulants (NOACs) are indicated for stroke prevention in atrial fibrillation (AF) but require lower doses in certain patients. We sought to describe the ...frequency, appropriateness (according to Food and Drug Administration labeling), and outcomes of patients prescribed reduced doses of NOACs in community practice.
Methods and Results
We analyzed data from the ORBIT‐AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) registry, a prospective, national, observational registry of AF patients. Among 7925 AF patients receiving NOACs, we assessed patterns of use of reduced NOAC doses and associated cardiovascular and bleeding outcomes at median follow‐up of 1 year. Overall, 6636 patients (84%) received a NOAC at standard dose, which was consistent with US Food and Drug Administration labeling in 6376 (96%). Reduced NOAC dose was prescribed to 1289 (16% overall), which was consistent with Food and Drug Administration labeling in only 555 patients (43%). Compared with those whose NOAC dose was appropriately reduced, patients receiving inappropriate dose reductions were younger (median age 79 versus 84, P<0.0001) and had lower ORBIT bleeding risk scores (26% ≥4 versus 45%, P<0.0001). Compared with those appropriately receiving standard dosing, patients receiving inappropriately reduced‐dose NOACs had higher unadjusted rates of thromboembolic events (2.11 versus 1.35 events per 100 patient years, hazard ratio 1.56, 95% confidence interval 0.92‐2.67) and death (6.77 versus 2.60, hazard ratio 2.61, 95% confidence interval 1.86‐3.67). After adjustment, outcomes were not significantly different but tended to favor patients dosed appropriately.
Conclusions
The majority of dose reductions of NOACs in AF are inconsistent with US Food and Drug Administration recommendations. There appear to be opportunities to improve current NOAC dosing in community practice.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701817.
The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both ...the PDF and HTML versions of the Article.
In the initial report of the Lupron Depot Neoadjuvant Prostate Cancer Study Group patients who received 3 months of androgen deprivation had a significant decrease in the positive margin rate. We ...monitored these patients for 5 years and to our knowledge present the longest followup of any neoadjuvant trial.
A multi-institutional prospective randomized trial was performed between February 1992 and April 1994 involving patients with stage cT2b prostate cancer, including 138 who received 3 months of leuprolide plus flutamide before radical prostatectomy and 144 who underwent radical prostatectomy only. Patients were followed every 6 months with serum prostate specific antigen (PSA) testing for 5 years. Biochemical recurrence was defined as PSA greater than 0.4 ng./ml.
At 5 years there was no difference in the biochemical recurrence rate. PSA was less than 0.4 ng./ml. in 64.8% of the patients in the neoadjuvant androgen ablation plus prostatectomy and 67.6% in the prostatectomy only group (p = 0.663).
Although 3 months of androgen deprivation before radical prostatectomy resulted in an apparently significant decrease in positive surgical margins, a 5-year followup does not indicate any difference in the recurrence rate. Until studies document improvement in biochemical or clinical recurrence with longer periods of treatment, induction androgen deprivation before radical prostatectomy is not indicated.
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