tbuckley/cabot-search huggingface dataset:
A practical guide to methods controlling false discoveries in computational biology
Authors: Keegan Korthauer, Patrick K. Kimes, Claire Duvallet, Alejandro Reyes, Ayshwarya Subramanian, Mingxiang Teng, Chinmay Shukla, Eric J. Alm, Stephanie C. Hicks
Journal: Genome biology (2019)

In high-throughput studies, hundreds to millions of hypotheses are typically tested. Statistical methods that control the false discovery rate (FDR) have emerged as popular and powerful tools for error rate control. While classic FDR methods use only p values as input, more modern FDR methods have been shown to increase power by incorporating complementary information as informative covariates to prioritize, weight, and group hypotheses. However, there is currently no consensus on how the modern methods compare to one another. We investigate the accuracy, applicability, and ease of use of two classic and six modern FDR-controlling methods by performing a systematic benchmark comparison using simulation studies as well as six case studies in computational biology. Methods that incorporate informative covariates are modestly more powerful than classic approaches, and do not underperform classic approaches, even when the covariate is completely uninformative. The majority of methods are successful at controlling the FDR, with the exception of two modern methods under certain settings. Furthermore, we find that the improvement of the modern FDR methods over the classic methods increases with the informativeness of the covariate, total number of hypothesis tests, and proportion of truly non-null hypotheses. Modern FDR methods that use an informative covariate provide advantages over classic FDR-controlling procedures, with the relative gain dependent on the application and informativeness of available covariates. We present our findings as a practical guide and provide recommendations to aid researchers in their choice of methods to correct for false discoveries.
PB2315 ECHO HEART AND TISSUE DOPPLER ASSESSMENT AS EARLY PREDICTORS OF CARDIAC INJURIES IN SICKLE CELL PATIENTS
Authors: N. Sayed
Journal: HemaSphere (2019)

Background: Major cardiac abnormalities in patients with sickle cell disease are related to volume overload effects of chronic anemia and ferritin level. Patients with SCA have reduced LV global longitudinal strain. In the detection of subclinical LV dysfunction in patients presenting with sickle cell disease, 2D speckle tracking and tissue Doppler echocardiography appears to be useful to assess systolic dysfunction and diastolic dysfunction respectively. Aims: The aim of our study was to evaluate cardiac performance in adult Egyptian asymptomatic sickle cell patients. Methods: The study was conducted on 30 SCD patients who were recruited from the hematology clinic of Kasr El‐Ainy Hospital‐ Cairo University and 15 healthy control who were age and sex matched. Two‐dimensional speckle tracking echocardioghraphy (STE), M‐mode, Doppler and tissue Doppler echocardiography (TDE) were are used to assess systolic and diastolic dysfunction in both groups. We used parameters (GLS, AP3L, AP2L, AP4L, EF, LVIDS and LVIDd) for systolic dysfunction. And for diastolic dysfunction we used parameters (medial and lateral E/e’, E/A ratio, Dt and S velocity). Results: our results revealed significant increase in LVIDS and LVIDd dimensions in cases compared to control group (P &lt; 0.001). None had an ejection fraction below 55%. Diastolic dysfunction was elicited in 8 patients (26%). There was a statistically significant correlation between the serum ferritin level and lateral E/E’ ratio. There was a significant reduction in GLS (p value.026) and also apical segments longitudinal strain (p value.002) compared to control. There was statistically significant negative correlation between number of sickle cell crises per year and GLS (p = 0.040). There was a statistical significant inverse correlation between Global LV systolic function and hemoglobin level (p = 0.04). Summary/Conclusion: Cardiac performance should include assessment of both systolic and diastolic parameters as there could be alteration in LV diastolic filling indices even in absence of systolic dysfunction. Hence these indices can be used as an early marker for cardiac affection. Speckle tracking echocardiography can recognize the cardiac involvement in really early stages and initiation of treatment and decreasing rate of painful crises to prevent irreversible myocardial dysfunction.
SP0058 GROWING UP CHANGES EVERYTHING!
Authors: Iain McInnes
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> There is increasing interest in understanding the impact of age upon the emergence and clinical impact of immune mediated inflammatory diseases. In this lecture I will consider the similarities and distinctions between the presentation of inflammatory arthritis in children and adults. <h3>Disclosure of Interests:</h3> Iain McInnes Grant/research support from: AstraZeneca, Celgene, Compugen, Novartis, Roche, UCB Pharma, Consultant for: AbbVie, Celgene, Galvani, Lilly, Novartis, Pfizer, UCB Pharma
Reversion of the resistance to tamoxifen and cross-resistance to fulvestrant in a novel breast cancer cell line by inhibition of the PI3K/Akt/mTor signaling pathway
Authors: Sandra Ghayad, Julie Vendrell, Xavier Thomas, Charles Dumontet, Pascale Cohen
Journal: Cancer Research (2007)

2340  Cross-resistance to the different molecules used in endocrine therapy is one of the main challenges in the treatment of estrogen receptor positive (ER+) breast cancer patients. In patients with advanced breast cancer progressing on prior endocrine therapy with tamoxifen (Tam), the clinical benefit rate under fulvestrant used as second line treatment is 43.4%, meaning that cross-resistance to these two molecules is a future clinical challenge. In this work, we used an ER+ human breast carcinoma cell line derived from MCF-7 (MVLN cell line) and a yet uncharacterized MVLN-derived cell line selected under Tam, which developed resistance to Tam and strikingly, a cross-resistance to fulvestrant, phenomenon rarely observed. This resistant cell line is the first to be described mimicking the behavior of resistant cells selected under Tam treatment and cross-resistant to fulvestrant, and thus, is a very good model in the understanding of the acquired endocrine therapy cross-resistance. Elevated levels and/or constitutive activation of members of the PI3K/Akt/mTOR signalling pathway are found in breast cancer and were reported to be associated with endocrine resistance. Interestingly, we found that the IGF1R/PI3K/Akt/mTOR pathway was more activated in the resistant cells than in MVLN. Indeed, we observed in the resistant cells an increase in the protein expression of IGF1Rα and in the phosphorylation levels of Akt, Akt downstream targets (Bad and GSK3) and the mTOR substrate p70S6K. Moreover, phosphorylation level of ER alpha Ser-167, known as the putative target site for phosphorylation by Akt, was more elevated in these cells. Since the use of signal transduction inhibitors in the treatment of ER+ patients represents one of the most promising therapeutic approaches, we explored the impact of LY294002 (PI3K inhibitor) and rapamycin (mTOR inhibitor) on the pharmacological response to Tam and fulvestrant on both cell lines. We observed a potentialisation of the cytostatic effect of Tam in the MVLN cells when combined to LY294002 or to rapamycin. Most interestingly, we demonstrated that LY294002 restored both Tam and fulvestrant response in the resistant cells. Under rapamycin treatment, resistant cells appeared to be more sensitive to the growth inhibitory effect of this molecule than MVLN. Moreover, in the resistant cells, the addition of rapamycin led to the inhibition of the proliferative activity of Tam and bypassed the resistance to fulvestrant. Finally, we used the Affymetrix Human Genome U133 Plus 2.0 array to investigate gene expression profiles associated with rapamycin activity with or without fulvestrant. Taken together, our data should enhance our knowledge on the development of alternative therapeutic strategies to bypass endocrine resistance in the postmenopausal ER+ breast cancer patients.
SP0203 WHAT DOES REMISSION MEAN FOR PATIENTS?
Authors: Ruth Williams
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> What does remission in Rheumatoid arthritis mean to patient? This session discusses what remission means to patients. Remission holds different meaning for researchers, clinicians and patients. In addition it holds different meaning for individual patients and for individual patients at different points of time in their lives. I shall reflect on over fifty years living with Rheumatoid arthritis, as both a patient and a doctor. To consider the changes in my care, my therapy and in my own and my clinicians objectives and treatment aims, at different points in time. Looking at how things have progressed from pain relief, splinting, physical therapy, rehabilitation and surgery. To progressively more effective DMARD"s, antI-TNF"s &amp; Biologics and an aim of complete 'clinical remission". However commonly 'clinical remission" can conflict with a patients concept of remission, as patients are individuals and the tools used to define remission are research based and consider populations not people. 'Disease activity scoring" and 'Treat to Target" has had significant impact on patients, clinicians and their rheumatology consultations. The absence of inflammation does not equal remission for many patients and it is important to consider the differing needs of patients who were diagnosed pre and post- biologic therapies and those with refractory disease. Currently maximal energy appears to be concentrated on the newly diagnosed and even pre-diagnosis, but has this been at the detriment of those with long established disease? I will share my own and different patients viewpoints of what 'remission" means and consider the benefits of progress in effective 'therapies' but also to reflect upon some of the important things that may have been lost from clinical 'care" along the way. To list simple things that can help patients achieve remission that can easily be forgotten. I will explain the phenomenon of 'DAS blindness' and the potential failings it can lead to. Discuss how improved shared decision making of treatment aims might improve outcomes for patients whilst reducing risk and possibly costs; aiming to increase patient autonomy and improve the doctor patient dynamic. In order to achieve 'remission" for patients we need to have a clear shared understanding of what 'remission" means to each individual and only then can we aim to achieve it. <h3>Disclosure of Interests:</h3> None declared
PB2399 BETA THALASSEMIA MINOR PATIENTS: NOT TIRED, BUT DEPRESSED AND ANXIOUS
Authors: R. Eren, A. Karışmaz, C. Aslan, M. H. Doğu, S. Altındal, O. Yokuş, E. Suyanı
Journal: HemaSphere (2019)

Background: The quality of life has been influenced unfavourably and the prevalance of either depression or anxiety has been increased in beta thalassemia major (BTM) and beta thalassemia intermedia (BTI) patients. Yet, the studies including the quality of life in beta thalassemia minor (BTm) subjects are limited and just the depression was demonstrated to be frequent in individuals with BTm, compared to the healthy population. Likewise, the data regarding the presence of fatique and anxiety in adult BTm subjects is insufficient Aims: We aimed to investigate whether the severity of fatigue and the incidences of depression and anxiety of patients with BTm are different than healthy individuals using Fatigue Severity Scale (FSS) and Hospital Anxiety and Depression Scale (HADS). Methods: Seventy‐seven BTm subjects were included in this study. The individuals (n = 38) using any medications, alcohol or tobacco; and having any chronic diseases and sleeping disturbances, were excluded. The remaining 39 BTm subjects were enrolled in the study. They had also normal biochemical parameters, thyroid function tests and C‐reactive protein (CRP). Twenty‐five healthy control subjects who were matched with age, sex, marital status, educational status and body mass index (BMI), were also included. Results: The BTm and the control groups were comparable in terms of gender, age, BMI, educational status and marital status (p = 0.368, 0.755, 0.851, 0.785, 0.709 respectively) (Table 1). Fatigue Severity Scale score was ≥4 in 23 (59.0%) BTm subjects and in 15 (60%) control subjects (p = 1.0). HADS anxiety score was ≥10 in 20 (51.3%) BTm subjects and in 5 (20.0%) control subjects (p = 0.018) and HADS depression score was ≥ 7 in 20 (51.3%) BTm subjects and 6 (24.0%) healthy control subjects (p = 0.039). There was no correlation of hemoglobin with FSS score (p = 0.526, r = ‐0.105), HADS anxiety score (p = 0.703, r = ‐0.063) or HADS depression score (p = 0.718, r = ‐0.06) in BTm group (Table 2). Summary/Conclusion: We found that both depression and anxiety were higher in BTm patients than healthy individuals, but this difference was not feasible for fatigue. image image
Targeting intracellular, multi-drug resistant Staphylococcus aureus with guanidinium polymers by elucidating the structure-activity relationship
Authors: Agnès Kuroki, Arnaud Kengmo Tchoupa, Matthias Hartlieb, Raoul Peltier, Katherine E.S. Locock, Meera Unnikrishnan, Sébastien Perrier
Journal: Biomaterials (2019)
S820 FRONTLINE BRENTUXIMAB VEDOTIN WITH CHEMOTHERAPY FOR STAGE 3/4 CLASSICAL HODGKIN LYMPHOMA: 3‐YEAR UPDATE OF THE ECHELON‐1 STUDY
Authors: A. Gallamini, D. Straus, M. Dlugosz‐Danecka, S. Alekseev, A. Illes, M. Picardi, E. Lech‐Maranda, T. Feldman, P. Smolewski, K. Savage, N. Bartlett, J. Walewski, R. Ramchandren, P. Zinzani, J. Connors, H. Jolin, R. Liu, K. Fenton, N. Josephson, J. Radford
Journal: HemaSphere (2019)

Background: The phase 3 ECHELON‐1 study (NCT01712490) demonstrated that brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (A+AVD) was superior to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), in terms of modified progression‐free survival (PFS) per independent review and per investigator, for the frontline treatment of stage 3/4 classical Hodgkin lymphoma (cHL) (Connors JM, et al. N Engl J Med 2018;378: 331–344). The RATHL, and SWOG S0816 studies utilized positron‐emission tomography (PET) scan‐adapted strategies performed after cycle 2 (PET2), demonstrating short‐ and long‐term toxicities in PET2‐positive (PET2+) patients switched to bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), or escalated BEACOPP, and frequent relapses in PET2‐negative (PET2‐) patients. Long‐term follow‐up of patients with stage 3/4 disease who were aged ≤60 years in the RATHL and SWOG S0816 studies demonstrated 3‐year PFS of 79.8% (PET2‐, 82.1%), and 5‐year PFS of 74% (PET2‐, 76%), respectively. Aims: Here we present a 3‐year update of the ECHELON‐1 study to compare the effects of frontline A+AVD vs ABVD in patients with stage 3/4 cHL, including PFS per investigator and outcomes by PET status for the intention‐to‐treat (ITT) population. Methods: Patients with stage 3/4 cHL were randomized 1:1 to receive up to six cycles of A+AVD (n = 664) or ABVD (n = 670). Interim PET2 was conducted, patients with Deauville score of 5 at PET2 were allowed to switch to an alternative therapy. All analyses of PFS are exploratory and per investigator assessment. Results: At a median follow‐up of 37 months, analysis of PFS in the ITT population favored the A+AVD treatment arm (Table), with a 3‐year PFS of 83.1% for A+AVD vs 76.0% for ABVD; the 3‐year PFS values for PET2‐ patients aged &lt;60 years were 87.2% vs 81.0%, respectively. A trend toward benefit for PET2+ patients aged &lt;60 years treated with A+AVD was also observed, with a 3‐year PFS of 69.2% vs 54.7% with ABVD. Data from subgroups, together with safety follow‐up, including for peripheral neuropathy, will be presented. Summary/Conclusion: Follow‐up at 3 years demonstrates that frontline treatment of stage 3/4 cHL with A+AVD provides a durable treatment benefit compared with ABVD that is independent of PET2 status. While direct comparisons cannot be made, efficacy with A+AVD appears favorable in the context of findings with PET‐adapted strategies, without requiring interim PET assessment, escalation of therapy, or bleomycin. image
In high-risk patients with cancer, thromboprophylaxis with rivaroxaban did not reduce VTE events at 180 days
Authors: Andrea Cervi, James Douketis
Journal: Annals of Internal Medicine (2019)

ACP Journal Club18 June 2019In high-risk patients with cancer, thromboprophylaxis with rivaroxaban did not reduce VTE events at 180 daysAndrea Cervi, MD, James Douketis, MDAndrea Cervi, MDMcMaster University, Hamilton, Ontario, Canada (A.C., J.D.)Search for more papers by this author, James Douketis, MDMcMaster University, Hamilton, Ontario, Canada (A.C., J.D.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJ201906180-067 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationKhorana AA, Soff GA, Kakkar AK, et al; CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019;380:720-8 https://pubmed.ncbi.nlm.nih.gov/30786186Clinical Impact RatingsOncology: References1 Farge D, Bounameaux H, Brenner B, et al. International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2016;17:e452-66. [PMID: 27733271] Google Scholar2 Lyman GH, Bohlke K, Khorana AA, et al; American Society of Clinical Oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol. 2015;33:654-6. [PMID: 25605844] Google Scholar3 Carrier M, Abou-Nassar K, Mallick R, et al; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380:711-9. [PMID: 30511879] Google Scholar Author, Article, and Disclosure InformationAffiliations: McMaster University, Hamilton, Ontario, Canada (A.C., J.D.)This article was published at Annals.org on 4 June 2019. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 June 2019Volume 170, Issue 12Page: JC67KeywordsDeep vein thrombosisHemorrhageIntent to treat analysisLymphomaOutpatientsProphylaxisPulmonary embolismSafetyUltrasound imagingVenous thromboembolism ePublished: 18 June 2019 Issue Published: 18 June 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
THU0665 PREVALENCE OF RHEUMATIC DISEASES IN COLOMBIA: AN APPROACH FROM MINISTRY OF HEALTH AND SOCIAL PROTECTION DATA (SISPRO)
Authors: Daniel G. Fernández-Ávila, Santiago Bernal-Macias, Diana Rincón, Juan Gutiérrez
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The ministry of health and social protection of Colombia uses a system named SISPRO as a tool to establish the basic information of the health system. This information is public and available for anyone to search. We analyze the prevalence and specific characteristics of patients with rheumatic diseases registered in colombian health system between 2012 to 2016. <h3>Objectives:</h3> To establish the prevalence and basic epidemiological characteristics of the main rheumatic diseases in Colombia <h3>Methods:</h3> This is a descriptive epidemiological study using the International Statistical Classification of Diseases and Related Health Problem (CDI), as keywords for each rheumatic disease during the analysis of SISPRO data and National Statistical System (DANE) populations projections, as from the last census in Colombia to estimated prevalence of each disease. <h3>Results:</h3> Colombia is a middle-income country with an estimated population of 49.834.240 habitants to 2018 according to 2005 census projections. Despite some limitations of SISPRO data, actually is the only official database of the government. We calculate the estimated prevalence and number of patients with some rheumatic diseases (table 1), confirming that autoimmune diseases are more frequent in woman, and surprisingly, spondyloarthritis (ankylosing, psoriasis and inflammatory bowel disease) are also discreetly more frequent in woman population. <h3>Conclusion:</h3> Epidemiological and prevalence information of rheumatic diseases in Colombia is presented. The data found in the present study are concordant with epidemiological studies in other countries. <h3> Disclosure of Interests:&nbsp;:</h3> None declared
FRI0138 EXPOSURE-RESPONSE ANALYSES OF UPADACITINIB EFFICACY AND SAFETY IN RHEUMATOID ARTHRITIS – ANALYSES OF PHASE 2 AND 3 STUDIES
Authors: Mohamed-Eslam Mohamed, Ahmed Nader, Insa Winzenborg, Eva Doelger, Peter Noertersheuser, Aileen Pangan, Ahmed Othman
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Upadacitinib (UPA), an oral selective JAK1 inhibitor, demonstrated favorable efficacy and acceptable safety in two Phase 2 and five Phase 3 global studies in subjects with moderately to severely active rheumatoid arthritis (RA). <h3>Objectives</h3> To characterize relationships between UPA plasma exposures and different efficacy and safety endpoints using data from Phase 2 and Phase 3 RA studies. <h3>Methods</h3> Analyses were conducted using data from 3685 (for efficacy) and 4577 (for safety) subjects with RA enrolled in the Phase 2 and 3 studies. Relationships between UPA plasma concentrations and efficacy and selected clinically relevant safety endpoints were analyzed using Markov Chain models and logistic regression analyses, respectively. <h3>Results</h3> Percentage of subjects achieving ACR20, ACR50, AC70, DAS28(CRP) ≤ 3.2, and DAS28(CRP) &lt; 2.6 increased with increasing UPA exposures, with maximum efficacy reached at exposures of 15 mg to 30 mg QD. Model-estimated efficacy responses are presented in Table 1. No relationships were observed between UPA exposure and pneumonia, herpes zoster infection, changes in platelet count (platelets ≥600×10<sup>9</sup>/L, platelets &gt;400×10<sup>9</sup>/L), lymphopenia (Grade 4 or higher), and neutropenia (Grade 3 or higher) at Week 12/14 or Week 24/26. Shallow trends for exposure-response relationships were observed for &gt; 2 g/dL decrease in hemoglobin from baseline at Week 12/14 and Week 24/26, lymphopenia Grade 3 or higher at Week 12/14, and serious infections at Week 24/26. No relationship with UPA exposure was observed for Grade 3 or higher lymphopenia at Week 24/26 (Figure 1). <h3>Conclusion</h3> Exposure-efficacy analyses demonstrate that UPA 15 mg QD dose maximizes efficacy in RA while 30 mg QD dose provides only a small (≤ 5%) additional incremental efficacy benefit. This was consistent across RA populations and whether UPA is used as monotherapy or on background treatment of csDMARDs. UPA plasma exposures associated with 15 mg and 30 mg QD dosing are predicted to have limited effects on the evaluated safety endpoints after 24 to 26 weeks of treatment. <h3>References</h3> [1] Genovese, et al. Lancet. 2018; 391(10139): 2513-2524. [2] Burmester, et al. Lancet. 2018; 391(10139): 2503-2512. [3] Mohamed et al. Clin Pharmacol Drug Dev. 2018 Apr 24. <h3>Disclosure of Interests</h3> Mohamed-Eslam Mohamed Shareholder of: AbbVie, Employee of: AbbVie, Ahmed Nader Shareholder of: AbbVie, Employee of: AbbVie, Insa Winzenborg Shareholder of: AbbVie, Employee of: AbbVie, Eva Doelger Shareholder of: AbbVie, Employee of: AbbVie, Peter Noertersheuser Shareholder of: AbbVie, Employee of: AbbVie, Aileen Pangan Shareholder of: AbbVie, Employee of: AbbVie, Ahmed Othman Shareholder of: AbbVie, Employee of: AbbVie