Abstract Background Mendelian randomization (MR) studies are susceptible to metadata errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control (QC) pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods We collated summary association statistics from fatty acid and cancer genome-wide association studies (GWAS) and subjected the collated data to a comprehensive QC pipeline. We identified metadata errors through comparison of study-specific statistics to external reference data sets (the National Human Genome Research Institute-European Bioinformatics Institute GWAS catalogue and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: (i) GWAS hits for fatty acids, (ii) GWAS hits for cancer and (iii) a 1000 genomes reference set. Results We collated summary data from 6 fatty acid and 54 cancer GWAS. Metadata errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (11.6%). After resolving metadata errors and analytical issues, we created a data set of 219 842 genetic associations with 90 cancer types, generated in analyses of 566 665 cancer cases and 1 622 374 controls. Conclusions In this large MR collaboration, 11.6% of included studies were affected by a substantial metadata error or analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of downstream MR analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).
Background and Aim: The etiology of liver diseases has changed in recent years, but its impact on the comparative burden of liver cancer between males and females is unclear. We estimated sex differences in the burden of liver cancer across 204 countries and territories from 2010 to 2019. Approach and Result: We analyzed temporal trends in the burden of liver cancer using the methodology framework of the 2019 Global Burden of Disease study. We estimated annual frequencies and age‐standardized rates (ASRs) of liver cancer incidence, death, and disability‐adjusted life‐years (DALYs) by sex, country, region, and etiology of liver disease. Globally in 2019, the frequency of incident cases, deaths, and DALYs due to liver cancer were 376,483, 333,672, and 9,048,723 in males, versus 157,881, 150,904, and 3,479,699 in females. From 2010 to 2019, the incidence ASRs in males increased while death and DALY ASRs remained stable; incidence, death, and DALY ASRs in females decreased. Death ASRs for both sexes increased only in the Americas and remained stable or declined in remaining regions. In 2019, hepatitis B was the leading cause of liver cancer death in males, and hepatitis C in females. From 2010 to 2019, NASH had the fastest growing death ASRs in males and females. The ratio of female‐to‐male death ASRs in 2019 was lowest in hepatitis B (0.2) and highest in NASH (0.9). Conclusions: The overall burden of liver cancer is higher in males, although incidence and death ASRs from NASH‐associated liver cancer in females approach that of males.
Historical Changes in Weight Classes and the Influence of NAFLD Prevalence: A Population Analysis of 34,486 Individuals
Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally in tandem with the growing obesity epidemic. However, there is a lack of data on the relationship between historical weight changes 10 years ago and at present on NAFLD prevalence at the population level. Therefore, we sought to evaluate the relationship between weight classes and the prevalence of NAFLD. Methods: Data were used from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Univariate and multivariate general linear model analyses were used to obtain risk ratio (RR) estimations of NAFLD events. Results: In total, 34,486 individuals were analysed, with those who were lean at both time points as the control group. Overweight (RR: 14.73, 95%CI: 11.94 to 18.18, p < 0.01) or obese (RR: 31.51, 95%CI: 25.30 to 39.25, p < 0.01) individuals at both timepoints were more likely to develop NAFLD. Residual risk exists where previously obese individuals became overweight (RR: 14.72, 95%CI: 12.36 to 17.52, p < 0.01) or lean (RR: 2.46, 95%CI: 1.40 to 4.31, p = 0.02), and previously overweight individuals who became lean (RR 2.24, 95%CI 1.42 to 3.54, p = 0.01) had persistent elevated risk of developing NAFLD despite weight regression. Sensitivity analysis identified that a higher proportion of individuals with regression in weight class were diabetics and Mexican Americans, while fewer African Americans saw weight-class regression. Conclusions: Residual risk exists in patients who lost weight despite the smaller magnitude of effect, and targeted weight reductions should still be used to mitigate the risk of NAFLD at the population level.
Natural History of Patients With Ischemia and No Obstructive Coronary Artery Disease
Background: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. Methods: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did. Results: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P <0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3–5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO ( P =0.46) or ISCHEMIA stress echocardiography participants ( P =0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029). Conclusions: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02347215.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss‐of‐function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org ).
Abemaciclib for pre/perimenopausal women with HR+, HER2- advanced breast cancer.
Abstract Background: A recent exploratory subgroup analysis pooling data from over 1000 patients (pts) in MONARCH 2 (final analysis) and MONARCH 3 (interim analysis) demonstrated that pts with clinical characteristics that predict for worse outcome (e.g. liver metastases, progesterone receptor [PgR]-negative status, high-grade tumors) received the largest benefit from the addition of abemaciclib to endocrine therapy (ET). There is also interest in determining the extent to which abemaciclib improves progression-free survival (PFS) in pts with favorable prognostic factors (e.g. bone-only disease, long treatment-free interval [TFI]). Here we present an update of the subgroup analyses of the MONARCH 3 study using data from the preplanned final PFS analysis. Methods: Enrollment criteria and study designs were previously described (Sledge et al. J Clin Oncol. 2017; Goetz et al. J Clin Oncol. 2017). An exploratory pooled analysis was conducted using data from MONARCH 2 (NCT02107703) and the MONARCH 3 (NCT02246621) preplanned final PFS analysis to identify significant prognostic factors regardless of therapy received. Using the updated MONARCH 3 data, PFS and objective response rate (ORR) (in pts with measurable disease) were examined within the prognostic subgroups that had been previously identified as being statistically significant. Additionally, subpopulation treatment effect pattern plot (STEPP) methodology was used to evaluate the association between TFI following adjuvant ET and outcomes of NSAI alone or with abemaciclib. Results: Assessment of clinical factors from MONARCH 2 and MONARCH 3 (final PFS data) confirmed that the following factors remained significantly prognostic regardless of treatment received: bone-only disease, liver metastases, tumor grade, PgR status, and ECOG performance status. In MONARCH 3, prognosis was poor in pts with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to ET regardless of prognosis, pts with these three poor prognostic factors received substantial benefit from abemaciclib, with PFS hazard ratios (HR) ranging from 0.4 to 0.5 and with differential improvement in ORR typically >30%. Furthermore, STEPP analysis of TFI (on the MONARCH 3 pts who had received adjuvant ET) demonstrated that pts who had a shorter TFI had a worse prognosis and received relatively greater benefit from abemaciclib plus NSAI than did pts with a longer TFI. Patients with bone-only disease or a long TFI also received benefit from abemaciclib, but to a relatively lesser extent (HR ranging from approximately 0.6 to 0.8). Conclusions: This exploratory analysis of the preplanned final PFS data from MONARCH 3 confirms previous findings that pts with poor prognostic factors may receive relatively greater benefit from the addition of abemaciclib to ET. Citation Format: Joyce O'Shaughnessy, Matthew P. Goetz, George W. Sledge, Miguel Martin, Yong Lin, Tammy Forrester, Ian C. Smith, Angelo Di Leo, Stephen Johnston. The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3 [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 CT099.