Likelihood Ratio Test P-value Research Articles

Bleb vessel density as a predictive factor for surgical revisions after Preserflo Microshunt implantation.

Bleb failure is a common complication after glaucoma filtration surgery. Different bleb classification schemes incorporating filtration bleb vascularization have been proposed, but the reported correlation with intraocular pressure (IOP) has been variable, possibly because of subjective vascularization grading. The purpose of the present study was to evaluate bleb vascularization after Preserflo Microshunt (PM) implantation using anterior segment OCT-angiography (AS-OCTA) as a biomarker for bleb failure. Twenty-three eyes of twenty-three patients underwent PM implantation. Up to 12 months after surgery PM scleral passage-centred AS-OCTA measurements (PLEX Elite 9000) for bleb-vessel density (BVD) determination were performed and IOP as well as necessity for surgical revisions (needling and open revision) were documented. After multi-step image analysis (region of interest definition, artefact removal, binarization, BVD calculation), the predictive value of early postoperative BVD for surgical revisions was assessed using logistic regression modelling. Baseline IOP (23.57 ± 7.75 mmHg) decreased significantly to 8.30 ± 2.12, 9.17 ± 2.33 and 11.70 ± 4.40 mmHg after 1, 2 and 4 week(s), and 13.48 ± 5.83, 11.87 ± 4.49, 12.30 ± 6.65, 11.87 ± 3.11 and 13.05 ± 4.12 mmHg after 2, 3, 6, 9 and 12 month(s), respectively (p < 0.001). Nine patients (39%) needed surgical revisions after a median time of 2 months. Bleb vessel densities at 2 and 4 weeks were significantly associated with future surgical revisions upon logistic regression analysis (2 W/4 W likelihood-ratio test p-value: 0.0244/0.0098; 2 W/4 W area under the receiver operating characteristics curve: 0.796/0.909). Filtration bleb vessel density can be determined using AS-OCTA in the early postoperative period and is predictive for bleb failure after PM implantation.

Assessing illness-related uncertainty in relapsing-remitting multiple sclerosis: A psychometric analysis of the Mishel Uncertainty of Illness Scale.

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p-value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS.

The value of NT-pro-brain natriuretic peptide and left ventricular ejection fraction for prediction of premature ventricular complexes burden.

We aimed to investigate the relation of NT-pro BNP level and left ventricular ejection fraction with premature ventricular complex burden. A total of 94 patients with PVC burden > 5% (age 45.9+12.9 years, 53 males, 41 females) were included in the study. The primary outcome was PVC burden % and main prognostic factors were LVEF% and NT-Pro BNP level. Gender, age, DM, HTN, presence of symptoms, symptom duration and heart rate were used as adjustment predictor variables. We created four different linear multivariable models to compare performance measures of prognostic factors: Model-1 has gender, age, DM, HTN, symptoms and heart rate, while LVEF has been added in addition to model-1 in model-2. Model-3 included NT-Pro-BNP alongside model-1 variables, while model-4 included both LVEF and NT-Pro-BNP variables in addition to model-1 variables. Accordingly, we compare the performance (R2, likelihood ratio X2) of models. The median PVC burden was 18% (IQR; 11-27). When model-1 consisting of gender, age, DM, HTN, presence of symptoms, symptomS duration and heart rate and model-2 consisting of LVEF in addition to variables of model-1 were compared, it was observed that both LRX2 and R2 values improved (likelihood ratio test p-value=0.013). Model-1 compared with model-3 which consisting of NT-pro BNP in addition to variables of model-1, and it was observed that both LRX2 and R2 values improved (likelihood ratio test p-value=0.008). However, when compared to model-1, the most significant improvement was observed in both LRX2 and R2 values in model-4 consisting of model-1 plus NT-Pro-BNP and LVEF (likelihood ratio test p-value <0.001). We determined that NT-pro-BNP levels and LVEF could predict PVC burden in patients. Higher levels of NT-pro-BNP and lower LVEF values were associated with increased PVC burden.

Joint effect of highly-sensitive cardiac troponin T and ankle-brachial index on incident cardiovascular events: The MESA and CHS

BackgroundElevated highly-sensitive cardiac troponin-T (hs-cTnT≥14 ng/L) and low ankle-brachial index (ABI<0.9) are risk factors for atherosclerotic cardiovascular diseases (ASCVD) but their joint effect on the risk of ASCVD events is unknown. MethodsWe used data from the two population-based cohort studies, the Multi-Ethnic study of Atherosclerosis (MESA) and Cardiovascular Heart Study (CHS) among 10,897 participants free of CVD events at baseline (mean age 66.3 years, 44.7% males). Incident ASCVD was defined as CHD (fatal/non-fatal MI or revascularization), transient ischemic attack, or stroke,. Hazard ratio (HR) and 95% CI was calculated from a Cox regression model. Interaction on the additive scale was assessed using relative excess risk due to interaction (RERI) and interaction on the multiplicative scale was assessed by Likelihood ratio (LR) test. ResultsAt baseline (2000–2002 for MESA and 1989–1990 for CHS), 10.2% of participants had elevated hs-cTnT and 7.5% had low ABI. During a median follow-up of 13.6 years (interquartile range, 7.5–14.7 years), there were 2590 incident ASCVD and 1542 incident CHD events. The hazard of CHD and ASCVD was higher in participants with both elevated hs-cTnT and low ABI [HR(95% CI): CHD: 2.04 (1.45, 2.88), ASCVD: 2.05 (1.58, 2.66)] than those with only elevated hs-cTnT [CHD: 1.65 (1.37, 1.99), ASCVD: 1.67 (1.44, 1.99)] or only low ABI [CHD: 1.87 (1.52, 2.31), ASCVD: 1.67 (1.42, 1.97)]. Antagonistic multiplicative interaction was observed for CHD (LR test p-value=0.042) but not for ASCVD (LR test p-value =0.08). No significant additive interaction was detected for CHD and ASCVD (RERI p-value ≥0.23). ConclusionThe observed joint effect of elevated cTnT and low ABI on ASCVD risk was smaller (i.e., antagonistic interaction) than that expected by the combined independent effects of each risk factor.

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study.

Simple SummaryResearch interest in Immuno-oncology and the role of the adaptative immune system in the progression and prognosis of colon cancer (CC) is growing. In this study, we evaluated the prognostic value of the consensus Immunoscore in 423 patients with AJCC/UICC-TNM stages I–III CC from Asian care centers. Immunoscore (IS) is a bench-to-digital pathology assay that quantifies CD3+ and cytotoxic CD8+ T-lymphocyte densities within the tumor and its invasive margin, stratifying patients into three categories: Low IS, Intermediate IS, and High IS. Multivariable Cox models stratified by center were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders, including gender, T-stage, N-stage, sidedness, and MSI. A comparison of the performance of risk prediction models was performed using the likelihood ratio test p-value. In uni/multivariable analyses, a High Immunoscore was significantly associated with prolonged survival of CC patients within the Asian population.BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I–III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I–III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75−30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10–4.55) p = 0.0269) of the patient’s gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27−9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35−5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21−5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39−6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.

The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome

BackgroundMucopolysaccharidosis IVA (Morquio syndrome A, MPS IVA) is an autosomal recessive lysosomal storage disorder caused due to biallelic variants in the N-acetylgalactoseamine-6-sulfate sulfatase (GALNS) gene. The mutation spectrum in this condition is determined amongst sub-populations belonging to the north, south and east India geography, however, sub-populations of west Indian origin, especially Gujarati-Indians, are yet to be studied. We aimed to analyse the variants present in the GLANS gene amongst the population of Gujarat by sequencing all exons and exon–intron boundaries of the GALNS gene in patients from 23 unrelated families.ResultsWe report 11 variants that include eight missense variants: (p.L36R, p.D39G, p.P77R, p.C79R, pP125L, p.P151L, p.G255A and p.L350P), one splice site variant: (c.121-7C > G), one small insertion: (c.1241_1242insA, p.I416HfsTer2) and one small deletion: (c.839_841delACA). Of these, three missense variants (p.D39G, p.G255A and p.L350P), one splice site and the two indels mentioned above are novel. Interestingly, we observed a higher than anticipated prevalence of p.P77R variant in our cohort (n = 14/25, 56%). Haplotype analysis in cases with p.P77R variant and 63 ethnicity matched healthy population controls suggested a 4 SNP haplotype block present in cases compared to controls (likelihood ratio test p-value = 1.16 × 10–13), thereby suggesting p.P77R variant as a founder variant in the Gujarati-Indian population. Furthermore, age of mutation analysis suggested the variant to have arisen approximately 450 years ago in the population.Conclusionp.P77R variant in the GLANS gene is likely to be a founder variant in MPS IVA patients of Gujarati-Indian ancestry and appeared approximately 450 years ago in the population. To our knowledge, this is the first variant to be posited as a founder variant in the GLANS gene in patients with MPS IVA syndrome.

Association between Outdoor Air Pollution Exposure and Handgrip Strength: Findings from the French CONSTANCES Study.

Association between Outdoor Air Pollution Exposure and Handgrip Strength: Findings from the French CONSTANCES Study.

Abstract MP76: Association Of Elevated High-sensitive Cardiac Troponin T And Low Ankle-brachial Index With Incident Cardiovascular Events. The Multi-ethnic Study Of Atherosclerosis And The Cardiovascular Health Study

Introduction: Elevated high-sensitive cardiac troponin T (hs-cTnT&gt;14 ng/L) and low ankle-brachial index (ABI &lt; 0.9) are known to be associated with cardiovascular diseases (CVD) but their joint effect on the risk of CVD events is unknown. Methods: We used data from the MESA and CHS among 10,900 participants free of CVD events at baseline (mean age 66.3 years, 44.7% males). Incident coronary heart disease (CHD) was defined as fatal or non-fatal myocardial infarction or revascularization and incident CVD was defined as CHD, transient ischemic attack, stroke, or atrial fibrillation. Hazard ratio (HR) and 95% CI was calculated from a Cox regression model. Interaction on the additive scale was assessed using relative excess risk due to interaction (RERI) and interaction on the multiplicative scale was assessed by Likelihood ratio (LR) test. Results: At baseline (2000-2002 for MESA and 1989-1990 for CHS), 10.2% of participants had elevated hs-cTnT and 7.5% had low ABI. During 26.1 years of total follow-up (median follow-up 18.4 years), there were 3,911 incident CVD events. The risk of CHD and CVD was higher in participants with both elevated hs-cTnT and low ABI [CHD HR: 2.1 (1.5, 2.9), CVD HR: 2.1 (1.7, 2.5)], only elevated hs-cTnT [CHD HR: 1.7 (1.4, 2.0), CVD HR: 1.6 (1.5, 1.8)], and only low ABI [CHD HR: 1.8 (1.5, 2.2), CVD HR: 1.5 (1.3, 1.7)] than those with unelevated hs-cTnT and normal ABI. Interaction on the multiplicative scale was observe in both adjusted and unadjusted models for CHD (unadjusted LR test p-value=0.002, adjusted LR test p-value=0.042) and only in unadjusted model for CVD (LR test p-value=0.001). No significant additive interaction was detected for both CHD and CVD (RERI p-value≥0.25 for unadjusted and adjusted models). Conclusion: Having both elevated cTnT and low ABI was associated more strongly with CVD events than only elevated cTnT or low ABI. Antagonistic multiplicative interaction was found indicating the observed joint effect of elevated cTnT and low ABI was smaller than the expected combined individual effects.

Uncovering associations between data-driven learned qMRI biomarkers and chronic pain

Knee pain is the most common and debilitating symptom of knee osteoarthritis (OA). While there is a perceived association between OA imaging biomarkers and pain, there are weak or conflicting findings for this relationship. This study uses Deep Learning (DL) models to elucidate associations between bone shape, cartilage thickness and T2 relaxation times extracted from Magnetic Resonance Images (MRI) and chronic knee pain. Class Activation Maps (Grad-CAM) applied on the trained chronic pain DL models are used to evaluate the locations of features associated with presence and absence of pain. For the cartilage thickness biomarker, the presence of features sensitive for pain presence were generally located in the medial side, while the features specific for pain absence were generally located in the anterior lateral side. This suggests that the association of cartilage thickness and pain varies, requiring a more personalized averaging strategy. We propose a novel DL-guided definition for cartilage thickness spatial averaging based on Grad-CAM weights. We showed a significant improvement modeling chronic knee pain with the inclusion of the novel biomarker definition: likelihood ratio test p-values of 7.01 × 10–33 and 1.93 × 10–14 for DL-guided cartilage thickness averaging for the femur and tibia, respectively, compared to the cartilage thickness compartment averaging.

Reconceptualizing the p-value from a likelihood ratio test: a probabilistic pairwise comparison of models based on Kullback-Leibler discrepancy measures

Discrepancy measures are often employed in problems involving the selection and assessment of statistical models. A discrepancy gauges the separation between a fitted candidate model and the underlying generating model. In this work, we consider pairwise comparisons of fitted models based on a probabilistic evaluation of the ordering of the constituent discrepancies. An estimator of the probability is derived using the bootstrap. In the framework of hypothesis testing, nested models are often compared on the basis of the p-value. Specifically, the simpler null model is favored unless the p-value is sufficiently small, in which case the null model is rejected and the more general alternative model is retained. Using suitably defined discrepancy measures, we mathematically show that, in general settings, the likelihood ratio test p-value is approximated by the bootstrapped discrepancy comparison probability (BDCP). We argue that the connection between the p-value and the BDCP leads to potentially new insights regarding the utility and limitations of the p-value. The BDCP framework also facilitates discrepancy-based inferences in settings beyond the limited confines of nested model hypothesis testing.

Abstract A039: Lower cellular activation of cMET signaling network is associated with reduced recurrence risk in stage II colorectal cancer

Abstract Colorectal cancer (CRC) has one of the highest worldwide incidences and mortality rates. About 25% of stage II patients develop recurrence within 5 years. However, use of adjuvant chemotherapy yields minimal therapeutic benefit. Clinical decision-making in this population would be informed by prognostic and predictive biomarkers that help indicate more targeted interventions and/or intensified disease monitoring. Higher cMET expression has been shown to be a prognostic marker in CRC and has been evaluated as a drug target in several cancers, including CRC. cMET acts as the receptor for hepatocyte growth factor (HGF), and is associated with increased proliferation, migration and morphogenesis of epithelial cells via activation of multiple downstream pathways including PI3K/AKT, MAPK and the NF-kB pathways. Here, we investigated whether increased cellular expression of multiple markers in the cMET/adjacent pathways was correlated with clinical outcome. The study population consisted of 283 patients with stage II CRC, without neoadjuvant treatment. Using a multiplexed immunofluorescence method (MxIF) with cell-level quantification (Cell DIVETM, GE Healthcare), 41 biomarkers in the cMET, mTOR, MAPK and associated pathways, and lymphocyte markers were analyzed in an iterative sequence of staining, imaging and dye inactivation, followed by image registration, cell segmentation and biomarker intensity-quantitation. Poor quality images and cells were filtered based on poor segmentation and tissue quality following manual review. Images that did not perfectly register were also excluded. For epithelial cell analysis, all stromal cells were filtered, resulting in a total of 559,952 epithelial cells. K-means clustering was conducted on cMET and related pathways (cMET, pGSK3β, 4EBP1, p4EBP1, S6, pS6, pStat3, pp38MAPK, pNFkBp65, pNFkBp105, EGFR, pERK1/2, HER2, IGF1R, CA-IX, Glut1, SLC7A5 and Ki67). Cluster analysis identified 6 cell clusters with varying expression levels of cMET and other pathway markers. A cluster corresponding to low cMET network activation (cMETLow) was correlated with reduced risk of recurrence (cox pH model Likelihood ratio test p-value = 0.056). Furthermore, MMR proficient patients (who had a higher recurrence rate) had a significantly greater proportion of cells with elevated cMET and related pathway marker (cMETHigh) s(p= 0.007). They also had a significantly lower fraction of infiltrating helper T cells (CD3+CD4+, pvalue 0.076) and CD68+ cells in the epithelial region, compared to MMR deficient patients (p=0.005). Further research will include continuing in-depth analysis of MMR status, cMET pathway and lymphocyte response as well as the role of cellular heterogeneity. In summary, comprehensive cMET pathway analysis using a multiplexed single cell approach indicates for the first time an association between low cMET network activation and superior clinical outcomes. Citation Format: Elizabeth McDonough, Anup Sood, Fiona Ginty, Sanghee Cho, John Graf, Jochen Prehn, Philip Dunne, Andreas Lindner, Manuela Salvucci, Daniel Longley, Mark Lawler, Travis Hollmann, Jinru Shia. Lower cellular activation of cMET signaling network is associated with reduced recurrence risk in stage II colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A039. doi:10.1158/1535-7163.TARG-19-A039

Risk of bias over time in updates of Cochrane oral health reviews

ObjectivesTo assess the changes in the risk of bias (RoB) across different versions of the same Cochrane systematic review, and to identify characteristics of systematic reviews which may be associated with different RoB scores by means of regression analysis. MethodsWe examined changes in RoB ratings in domains of randomized controlled trials (RCTs) and controlled trials (CTs) included in original Cochrane systematic reviews and their updates published in oral health. First, we checked the number of domains assessed for RoB in the different versions of the systematic review. Then, we computed the percentage of different ratings of RoB (low, high and unclear) in these systematic review versions. All data selection, extraction and analysis were conducted independently and in duplicate by two assessors. Time trends were reported in the form of line graphs. We also assessed systematic review characteristics as predictors of RoB scores by means of regression analysis. ResultsA total of 173 reviews consisting of the original reviews and their updates were examined. The proportion of different ratings of RoB was kept stable over the different versions. However, in more recent versions, the proportion of unclear RoB slightly increased, and the proportion of high RoB decreased. Cochrane risk of bias domains were a significant RoB score predictor (Likelihood ratio test p-value < 0.001). ConclusionsMethodological improvements in RCTs and CTs included in Cochrane reviews are needed. This comprehensive information on the RoB trend may help oral health researchers improving the methodology related to specific domains. Clinical significanceMethodological improvements are necessary for primary studies included in Cochrane reviews in oral health. The increase of domains rated as unclear RoB is of concern and suggests that strategies should be developed to improve the level of communication between trialists and systematic reviewers.

A discussion on significance indices for contingency tables under small sample sizes.

Hypothesis testing in contingency tables is usually based on asymptotic results, thereby restricting its proper use to large samples. To study these tests in small samples, we consider the likelihood ratio test (LRT) and define an accurate index for the celebrated hypotheses of homogeneity, independence, and Hardy-Weinberg equilibrium. The aim is to understand the use of the asymptotic results of the frequentist Likelihood Ratio Test and the Bayesian FBST (Full Bayesian Significance Test) under small-sample scenarios. The proposed exact LRT p-value is used as a benchmark to understand the other indices. We perform analysis in different scenarios, considering different sample sizes and different table dimensions. The conditional Fisher’s exact test for 2 × 2 tables and the Barnard’s exact test are also discussed. The main message of this paper is that all indices have very similar behavior, except for Fisher and Barnard tests that has a discrete behavior. The most powerful test was the asymptotic p-value from the likelihood ratio test, suggesting that is a good alternative for small sample sizes.

Abstract LB-146: T cell receptor immunosequencing improves prediction of melanoma recurrence

Abstract Background: The prognosis of patients with early-stage melanoma remains poor with overall survival at 10 years below 40% in patients with stage IIC disease. The use of anti-PD-1 adjuvant therapy has improved outcomes for some, but the role of the immune system in early disease and selection of ideal candidates for checkpoint blockade require further elucidation. Clonality of the tumor T-cell repertoire, as measured by next-generation immunosequencing of T-cell receptors (TCRs), recently demonstrated its utility as a biomarker of response to anti-PD-1 therapy in metastatic melanoma. Here, we aim to evaluate its ability to predict recurrence in patients who underwent resection of primary melanomas. Methods: Biomarkers of progression free survival (PFS) were evaluated in a cohort of 72 archival FFPE tumors from subjects who were followed for a minimum of five years. Tumor TCR-beta clonality and infiltrating T-cell fraction (fraction of nucleated cells that are T-cells) were quantified by the immunoSEQ® Assay (Adaptive Biotechnologies) while Breslow thickness, ulceration, mitotic rate, and briskness of tumor infiltrating lymphocytes were assessed by histopathology. Results: T-cell fraction, but not clonality, was a robust independent variable in predicting PFS (Cox Proportional Hazard Ratio = 0.71, p-value = 0.007) after resection of primary melanomas in patients who were not treated with immunotherapy regimens. In a gradient boosted model, T-cell fraction was second only to Breslow thickness in weighted importance for predicting PFS, which together accounted for 60% of the model's classification power. Variables comprising the remaining 40% included ulceration, patient age, tumor stage, and mitotic rate, and, except for stage, generally correlated with Breslow thickness. T-cell fraction, however, was not correlated with any clinical or histopathological variable, including briskness. The bivariate model Cox Regression of Breslow thickness and T-cell fraction performed better than Breslow thickness alone in predicting PFS (Likelihood Ratio Test p-value = 0.03). Furthermore, patients with high T-cell fractions had delayed recurrence (median of 19 vs 9 months, high vs low T-cell fraction in melanomas &amp;gt; 2.5mm; median PFS not reached for melanomas &amp;lt; 2.5mm). Conclusion: Patients with high T-cell fractions in intermediate and high-thickness melanomas have a more favorable prognosis and may be ideal candidates for adjuvant immunotherapy to prolong PFS. These findings are currently being validated in an expanded cohort of archival samples. Disclaimers/disclosures: For Research Use Only. Not for use in diagnostic procedures. Partial financial support provided by Adaptive Biotechnologies. Citation Format: Julie A. Rytlewski, Wiebke Pruessmann, James Wilmott, Martin C. Mihm, Beatrice Dyring-Andersen, Rachael A. Clark, Erik Yusko, Alexandra Snyder, Harlan Robins, Richard Scolyer, Thomas S. Kupper. T cell receptor immunosequencing improves prediction of melanoma recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-146.

A retrospective case control study to investigate race level risk factors associated with horse falls in Irish point-to-point races

Horseracing as a high-risk sport can pose a significant risk to equine welfare. To date no epidemiological reviews of fall risk in horseracing have investigated the risks specific to point-to-point (PTP) racing. This study aimed to identify the main race level risk factors associated with horse falls in Irish PTP and to compare these to published findings for hurdle and steeplechase racing. The study used a retrospective case-control design. Relevant variables were identified and information was collated for all PTP races in the 2013/14 and 2014/15 seasons. Race-level variables were analysed through univariable analysis to inform multivariable model building. A final multivariable logistic regression model was refined, using fall/no fall as the dependent variable, through a backward stepwise process with variables retained if likelihood ratio test P-values were &lt;0.05. During the study period 1,358 PTP races were recorded, 727 races (54%) included at least one horse fall. The fall frequency noted during the current study was 88/1000 starts. Race category impacted the odds of a fall occurring with all categories of maiden races having increased odds of falls compared to open races. Maiden races for 6 year olds and 6 and 7 year olds had the greatest chance of falling with 6.9 times increased odds. The chance of a race containing a fall increased 38% for each additional runner and was reduced by 25% for every horse that pulled up during the race. Using a larger data set could enable further sub-models to be developed. In the current study some of the variables had a low number of cases and/or controls which limited the analysis. Retrospective analysis of fall risk exposed some risk factors that have been previously identified in hurdle and steeplechase racing. The variables identified could inform future research and interventions aimed at improving horse and jockey safety whilst racing.

Should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? correlation with outcome in biopsy cases treated conservatively.

The identification of perineural invasion (PNI) and extraprostatic extension (ECE) in prostate cancer (PC) biopsies is time consuming and can be difficult. Although this is required information in many datasets, there is little evidence on their effect on outcome in patients treated conservatively. Cases of PC were identified from three cancer registries in the UK from men with clinically localized prostate cancer diagnosed by needle biopsy from 1990–2003. The endpoint was prostate cancer death (DOD). Patients treated radically within 6 months, those with objective evidence of metastases or who had prior hormone therapy were excluded. Follow-up was through cancer registries up until 2012. Deaths were divided into those from PC and those from other causes, according to WHO criteria. 988 biopsy cases (6522 biopsy cores) were centrally reviewed by three uropathologists and assigned a Gleason score and Grade Group (GG). The presence of both PNI and ECE was recorded. Of 988 patients, PNI was present in 288 (DOD = 75) and ECE in 23 (DOD = 5). On univariable analysis PNI was highly significantly associated with DOD (hazard ratio [HR] 2.28, 95% CI: 1.68, 3.1, log-rank test p-value = 4.8 × 10–8), but ECE was not (log-rank test p-value = 0.334). On multivariable analysis with GG, serum PSA (per 10%), clinical stage and extent of disease (per 10%), PNI lost significance (HR 1.16, 95% CI: 0.83, 1.63, likelihood ratio test p-value = 0.371). The utility of routinely examining prostate biopsies for ECE and PNI is doubtful as it is not independently associated with higher grade, stage or prognosis.

Changing epidemiology of Pneumocystis pneumonia, Northern Ireland, UK and implications for prevention, 1 July 2011-31 July 2012.

There is a lack of consensus about which non-human immunodeficiency virus (HIV) patient groups would benefit from prophylaxis. Here, we analysed an enhanced Pneumocystis jirovecii database to describe the epidemiology of Pneumocystis pneumonia (PCP) and P. jirovecii colonizations in Northern Ireland (NI) with a view to identifying risk groups who may benefit from prophylaxis. We prospectively collected information on demographics, clinical severity and clinical features for all hospital inpatients in NI aged ≥18 years with P. jirovecii confirmed in any respiratory tract sample. We defined P. jirovecii colonization or PCP according to clinical symptoms and radiological findings. We compared P. jirovecii colonization to PCP using exact logistic regression and presented the odds ratios (OR), 95 % confidence intervals (CI) and likelihood ratio test P-values.Results/Key findings. Overall, 36/49 (73 %) of P. jirovecii detections were categorized as PCP. A total of 28/36 (78 %) were in non-HIV patients, of which 18 (64 %) had cancer. The odds of PCP compared to P. jirovecii colonization were eight times higher in those with current exposure to chemotherapy (OR 8.73; 95 % CI 0.84, ∞), 16 times higher for those diagnosed with HIV (OR 16.2; 95 % CI 1.71, ∞) and 12 times higher for those ever exposed to another immunosuppressive drug (OR 12.1; 95 % CI 1.94, ∞). The greatest burden of PCP is now in the non-HIV group, particularly cancer patients. We recommend increasing clinician awareness of PCP risk and strengthening prevention guidelines in non-HIV patients, and promoting the consideration of prophylaxis on a case-by-case basis.

Abstract 17184: Achievement Of LDL-cholesterol Reduction Targets is Associated With Reduced Cardiovascular Disease Risk Among Patients With Familial Hypercholesterolemia in a Large Electronic Medical Record Database

Introduction: Heterozygous familial hypercholesterolemia (FH) is common but under-recognized, with an estimated prevalence of 1:200-1:500 and an associated high risk of premature cardiovascular disease (CVD). Little is known regarding the association between change in low-density lipoprotein cholesterol (LDL-C) and long-term CVD risk in FH patients. We hypothesized that FH patients who achieved LDL-C &lt; 100 mg/dL or reduction ≥50% post-statin initiation would have reduced risk of non-fatal myocardial infarction (MI) or revascularization. Methods: Using Dutch Lipid Network criteria components, 174 “probable” and 125 “definite” FH patients with LDL-C measurements available before and after statin initiation were identified in the Vanderbilt de-identified electronic medical records (EMR) Synthetic Derivative database, 1996-2014. First non-fatal MI or revascularization was identified via validated EMR algorithm with positive predictive value=92%. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression models in relation to LDL-C levels (≥ vs. &lt;50% reduction or &lt; vs. &gt;100 mg/dL post-statin), adjusted for age, race, sex, blood pressure, smoking, and body mass index. Results: Mean (+/- SD) LDL-C levels prior to initiation of statin therapy were 207 (+/- 31) for probable and 304 (+/- 124) mg/dL for definite FH patients. Similar proportions of patients attained ≥50% reduction in LDL-C after statin initiation in both groups (24.1% and 26.4%), while 22.4% achieved LDL-C &lt; 100 mg/dL in the probable group compared to only 4.8% in the definite group. Over median follow-up of 5.4 years, 34 probable and 19 definite FH patients experienced non-fatal MI or revascularization. The HR (95% CI) among those with post-statin LDL-C &lt; 100 vs &gt;100 mg/dL was 0.59 (0.23-1.52) overall, with no evidence of effect modification by probable/definite FH status (likelihood ratio test (LRT) p-value=0.58). A similar pattern was observed for LDL-C change ≥50% vs &lt;50% (HR (95% CI) 0.58 (0.24-1.38), LRT p-value=0.44). Conclusions: In this small sample of FH patients, lowering LDL-C to &lt;100 mg/dL suggests a reduction in CVD risk, but few attained this LDL-C target. These results warrant further research in larger populations of this understudied condition.

Apolipoprotein B improves risk assessment of future coronary heart disease in the Framingham Heart Study beyond LDL-C and non-HDL-C.

Analyses using conventional statistical methodologies have yielded conflicting results as to whether low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) is the best marker of the apoB-associated risk of coronary heart disease. The aim of this study was to determine the additional value of apoB beyond LDL-C or non-HDL-C as a predictor of coronary heart disease. For each patient from the Framingham Offspring Cohort aged 40-75 years (n = 2966), we calculated the extent to which the observed apoB differed from the expected apoB based on their LDL-C or non-HDL-C. We added this difference to a Cox model predicting new onset coronary heart disease over a maximum of 20 years adjusting for standard risk factors plus LDL-C or non-HDL. The difference between observed and expected apoB over LDL-C or non-HDL-C was highly prognostic of future coronary heart disease events: adjusted hazard ratios 1.26 (95% confidence interval: 1.15, 1.37) and 1.20 (1.11, 1.29), respectively, for each standard deviation increase beyond expected apoB levels. When this difference between observed and expected apoB was added to standard coronary heart disease prediction models including LDL-C or non-HDL-C, prediction improved significantly (likelihood ratio test p-values <0.0001) and discrimination c-statistics increased from 0.72 to 0.73. The corresponding relative integrated discrimination improvements were 11% and 8%, respectively. apoB improves risk assessment of future coronary heart disease events over and beyond LDL-C or non-HDL-C, which is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

The Grand National: a review of factors associated with non-completion and horse-falls, 1990 to 2012

The Grand National (GN) attracts high profile press and subsequent public attention. This study aimed to establish if factors influential to non-completion, horse-falls and specific fence risk in the GN supported the measures implemented by the British Horseracing Authority (BHA) to improve equine welfare in the GN. Horse, jockey, trainer and race related factors associated with non-completion, horse-falls and horse-falls at specific fences of the GN were collated over a 22 year period from 1990 to 2012. Descriptive analysis calculated non-completion rates per year, according to age and reason for non-completion. The distribution of fallers during the race in relation to fence number, design and key feature fences were also determined. Univariable analysis informed multivariable model building to identify factors associated with non-completion (n=840) and horse-falls (n=514) in the GN. Two final logistic regression models were refined through a backward stepwise process with variables retained if likelihood ratio test P-values were &lt;0.05. Chi-square goodness of fit analyses evaluated fall risk at fence level. During the period investigated 347 horses completed the GN; the probability of a horse falling in the race was 0.24. The first fence, Becher's brook and drop fences increased the risk of falling compared to plain fences. Good-soft going increased the number of horses that completed the race and reduced the number of fallers suggesting this is the optimal ground condition for the race. GNs run at a faster than average speed increased the risk of horses not completing and falling. Inexperienced horses and jockeys show a greater risk of not completing and falling. Our work supports BHA measures implemented to improve safety in the GN; controlling speed, modifying fence design, promoting race experience and ground maintenance to produce good-soft going can increase completions and reduce falls, therefore enhancing equine welfare.