Urea Cycle Metabolites and Atrial Fibrillation or Heart Failure Risk: Two Case-Control Studies in the PREDIMED Trial

Abstract Objectives To prospectively analyze the associations between urea cycle metabolites and incident atrial fibrillation (AF) or heart failure (HF), and to evaluate the effect of a Mediterranean diet (MD) intervention on such associations. Methods We designed two nested case-control studies within the PREDIMED trial, a randomized controlled trial aimed to evaluate the effect of two MD interventions, supplemented with either extra virgin olive oil (EVOO) or nuts, on cardiovascular disease (CVD). Fasting blood samples were collected at baseline and urea cycle metabolites (arginine, citrulline, and ornithine) and methylarginines (asymmetric dimethylarginine/symmetric dimethylarginine ratio (ADMA/SDMA ratio)) were determined using liquid chromatography tandem mass spectrometry. We used conditional logistic regression models, adjusted for potential confounders, to analyze the associations between the metabolites and incident AF or HF. Potential interactions between metabolites and intervention (MD groups vs control group) were tested with the likelihood ratio test. Results The study population comprised a total of 1241 participants (509 cases) for AF case-control and 824 participants (326 cases) for HF case-control. Arginine was inversely associated with incident AF (OR per SD 0.83, 95% CI 0.73; 0.94) and HF (OR per SD 0.82, 95% CI 0.69; 0.97). Whereas ADMA/SDMA ratio was positively associated with AF (OR per SD 1.19, 95% CI 1.02; 1.41) but not with HF risk. A statistically significant interaction (P = 0.044) was found between arginine and intervention on HF risk. The lower risk of HF associated with arginine was only observed in participants of the MD groups (EVOO + nuts). Conclusions The results of the present study suggest that urea cycle metabolites, arginine and ADMA/SDMA ratio specifically, could be involved in AF and HF pathophysiology. Moreover, the dietary intervention may modify the association between arginine and HF. Funding Sources National Institutes of Health (NIH), Spanish Government Official Agency for funding biomedical research-Instituto de Salud Carlos III (ISCIII) and CIBEROBN

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Choline Metabolism and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Study

Clinical Chemistry ◽

10.1093/clinchem/hvaa224 ◽

2020 ◽

Author(s):

Christopher Papandreou ◽

Mònica Bulló ◽

Pablo Hernández-Alonso ◽

Miguel Ruiz-Canela ◽

Jun Li ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Multiple Testing ◽

Conditional Logistic Regression ◽

Case Control Studies ◽

Logistic Regression Models ◽

Liquid Chromatography Tandem Mass ◽

Nested Case Control ◽

Incident Cases ◽

Predimed Study

Abstract Background Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations. Methods Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvención con DIeta MEDiterránea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models. Results After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30–2.63) and 1.57 (1.09–2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99–1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03–1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57–4.03), 1.65 (1.00–2.71) and 1.65 (1.04–2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF. Conclusions Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF.

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Glycolysis Metabolites and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Trial

Metabolites ◽

10.3390/metabo11050306 ◽

2021 ◽

Vol 11 (5) ◽

pp. 306

Author(s):

Nerea Becerra-Tomás ◽

Miguel Ruiz-Canela ◽

Pablo Hernández-Alonso ◽

Mònica Bulló ◽

Jun Li ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Conditional Logistic Regression ◽

Negative Ion ◽

Plasma Metabolites ◽

Mediterranean Population ◽

Case Control Studies ◽

Increased Risk ◽

Glycolysis Pathway ◽

Negative Ion Mode

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case–control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR for 1 SD increase: 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies.

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A systematic assessment of the association between frequently prescribed medicines and the risk of common cancers: a series of nested case-control studies

BMC Medicine ◽

10.1186/s12916-020-01891-5 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

R. D. McDowell ◽

C. Hughes ◽

P. Murchie ◽

C. Cardwell

Keyword(s):

Cancer Risk ◽

Conditional Logistic Regression ◽

Exposure Dose ◽

Case Control ◽

Case Control Studies ◽

Systematic Assessment ◽

Exposure Response ◽

Prescribed Medicines ◽

Nested Case Control ◽

Novel Associations

Abstract Background Studies systematically screening medications have successfully identified prescription medicines associated with cancer risk. However, adjustment for confounding factors in these studies has been limited. We therefore investigated the association between frequently prescribed medicines and the risk of common cancers adjusting for a range of confounders. Methods A series of nested case-control studies were undertaken using the Primary Care Clinical Informatics Unit Research (PCCIUR) database containing general practice (GP) records from Scotland. Cancer cases at 22 cancer sites, diagnosed between 1999 and 2011, were identified from GP records and matched with up to five controls (based on age, gender, GP practice and date of registration). Odds ratios (OR) and 95% confidence intervals (CI) comparing any versus no prescriptions for each of the most commonly prescribed medicines, identified from prescription records, were calculated using conditional logistic regression, adjusting for comorbidities. Additional analyses adjusted for smoking use. An association was considered a signal based upon the magnitude of its adjusted OR, p-value and evidence of an exposure-response relationship. Supplementary analyses were undertaken comparing 6 or more prescriptions versus less than 6 for each medicine. Results Overall, 62,109 cases and 276,580 controls were included in the analyses and a total of 5622 medication-cancer associations were studied across the 22 cancer sites. After adjusting for comorbidities 2060 medicine-cancer associations for any prescription had adjusted ORs greater than 1.25 (or less than 0.8), 214 had a corresponding p-value less than or equal to 0.01 and 118 had evidence of an exposure-dose relationship hence meeting the criteria for a signal. Seventy-seven signals were identified after additionally adjusting for smoking. Based upon an exposure of 6 or more prescriptions, there were 118 signals after adjusting for comorbidities and 82 after additionally adjusting for smoking. Conclusions In this study a number of novel associations between medicine and cancer were identified which require further clinical and epidemiological investigation. The majority of medicines were not associated with an altered cancer risk and many identified signals reflected known associations between medicine and cancer.

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Oral Contraceptive Use and Breast Cancer Risk Assessment: A Systematic Review and Meta-Analysis of Case-Control Studies, 2009–2020

Cancers ◽

10.3390/cancers13225654 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5654

Author(s):

Agnieszka Barańska ◽

Agata Błaszczuk ◽

Wiesław Kanadys ◽

Maria Malm ◽

Katarzyna Drop ◽

...

Keyword(s):

Breast Cancer ◽

Oral Contraceptive ◽

Cancer Risk ◽

Meta Analysis ◽

Case Control ◽

Cochrane Library ◽

Control Group ◽

Case Control Studies ◽

Increased Risk ◽

Breast Cancer Risk Assessment

To perform a meta-analysis of case-control studies that addressed the association between oral contraceptive pills (OC) use and breast cancer (BrCa), PubMED (MEDLINE), Embase, and the Cochrane Library were searched to identify case-control studies of OC and BrCa published between 2009 and 2020. We used the DerSimonian–Laird method to compute pooled odds ratios (ORs) and confidence intervals (CIs), and the Mantel–Haenszel test to assess the association between OC use and cancer. Forty-two studies were identified that met the inclusion criteria and we included a total of 110,580 women (30,778 into the BrCa group and 79,802 into the control group, of which 15,722 and 38,334 were using OC, respectively). The conducted meta-analysis showed that the use of OC was associated with a significantly increased risk of BrCa in general, OR = 1.15, 95% CI: 1.01 to 1.31, p = 0.0358. Regarding other risk factors for BrCa, we found that increased risk was associated significantly with early menarche, nulliparous, non-breastfeeding, older age at first parity, postmenopause, obesity, smoking, and family history of BrCa. Despite our conclusion that birth control pills increase the cancer risk being supported by extensive previous studies and meta-analyzes, further confirmation is required.

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Association of FOXO3 Blood DNA Methylation with Cancer Risk, Cancer Survival, and Mortality

Cells ◽

10.3390/cells10123384 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3384

Author(s):

Chenglong Yu ◽

Allison M. Hodge ◽

Ee Ming Wong ◽

Jihoon Eric Joo ◽

Enes Makalic ◽

...

Keyword(s):

Lung Cancer ◽

Dna Methylation ◽

Cancer Risk ◽

Cancer Survival ◽

Conditional Logistic Regression ◽

B Cell Lymphoma ◽

Case Control ◽

Case Control Studies ◽

Cox Models ◽

Total N

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

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Effectiveness of seasonal malaria chemoprevention (SMC) treatments when SMC is implemented at scale: Case–control studies in 5 countries

PLoS Medicine ◽

10.1371/journal.pmed.1003727 ◽

2021 ◽

Vol 18 (9) ◽

pp. e1003727

Author(s):

Matthew Cairns ◽

Serign Jawo Ceesay ◽

Issaka Sagara ◽

Issaka Zongo ◽

Hamit Kessely ◽

...

Keyword(s):

Clinical Trials ◽

Malaria Control ◽

Conditional Logistic Regression ◽

Clinical Malaria ◽

Case Control ◽

The Gambia ◽

Personal Protection ◽

Case Control Studies ◽

Seasonal Malaria Chemoprevention ◽

Protective Effectiveness

Background Seasonal malaria chemoprevention (SMC) has shown high protective efficacy against clinical malaria and severe malaria in a series of clinical trials. We evaluated the effectiveness of SMC treatments against clinical malaria when delivered at scale through national malaria control programmes in 2015 and 2016. Methods and findings Case–control studies were carried out in Mali and The Gambia in 2015, and in Burkina Faso, Chad, Mali, Nigeria, and The Gambia in 2016. Children aged 3–59 months presenting at selected health facilities with microscopically confirmed clinical malaria were recruited as cases. Two controls per case were recruited concurrently (on or shortly after the day the case was detected) from the neighbourhood in which the case lived. The primary exposure was the time since the most recent course of SMC treatment, determined from SMC recipient cards, caregiver recall, and administrative records. Conditional logistic regression was used to estimate the odds ratio (OR) associated with receipt of SMC within the previous 28 days, and SMC 29 to 42 days ago, compared with no SMC in the past 42 days. These ORs, which are equivalent to incidence rate ratios, were used to calculate the percentage reduction in clinical malaria incidence in the corresponding time periods. Results from individual countries were pooled in a random-effects meta-analysis. In total, 2,126 cases and 4,252 controls were included in the analysis. Across the 7 studies, the mean age ranged from 1.7 to 2.4 years and from 2.1 to 2.8 years among controls and cases, respectively; 42.2%–50.9% and 38.9%–46.9% of controls and cases, respectively, were male. In all 7 individual case–control studies, a high degree of personal protection from SMC against clinical malaria was observed, ranging from 73% in Mali in 2016 to 98% in Mali in 2015. The overall OR for SMC within 28 days was 0.12 (95% CI: 0.06, 0.21; p < 0.001), indicating a protective effectiveness of 88% (95% CI: 79%, 94%). Effectiveness against clinical malaria for SMC 29–42 days ago was 61% (95% CI: 47%, 72%). Similar results were obtained when the analysis was restricted to cases with parasite density in excess of 5,000 parasites per microlitre: Protective effectiveness 90% (95% CI: 79%, 96%; P<0.001), and 59% (95% CI: 34%, 74%; P<0.001) for SMC 0–28 days and 29–42 days ago, respectively. Potential limitations include the possibility of residual confounding due to an association between exposure to malaria and access to SMC, or differences in access to SMC between patients attending a clinic and community controls; however, neighbourhood matching of cases and controls, and covariate adjustment, attempted to control for these aspects, and the observed decline in protection over time, consistent with expected trends, argues against a major bias from these sources. Conclusions SMC administered as part of routine national malaria control activities provided a very high level of personal protection against clinical malaria over 28 days post-treatment, similar to the efficacy observed in clinical trials. The case–control design used in this study can be used at intervals to ensure SMC treatments remain effective.

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Association between anxiety symptoms and atrial fibrillation in a community cohort of Chinese older adults: a case-control study

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02278-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhu-Xia Shen ◽

Yu-Min Sun ◽

Hui-Hui Gu ◽

Yan Zhang ◽

Zhi-Wen Shen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Older Adults ◽

Heart Disease ◽

Odds Ratio ◽

Case Control Study ◽

Case Control ◽

Anxiety Symptoms ◽

Control Group ◽

Community Based ◽

Control Study

Abstract Background The association between anxiety and atrial fibrillation (AF) remains unclear. Moreover, this association has rarely been studied in Chinese individuals aged 60 years or older. This study investigated the association between anxiety and AF in a community-based case-control study of older adult residents in urban China. Methods The cases and controls were from a community-based study conducted in the Jingansi community in Shanghai, China, between January 2010 and December 2012. A total of 3622 residents aged 60 years or older without severe vision, hearing, or speaking impairments were eligible to participate in the physical examinations and questionnaire survey. AF was assessed based on a previous physician’s diagnosis, electrocardiogram, ambulatory electrocardiogram, or echocardiogram. Anxiety was evaluated using the Zung Self-Rating Anxiety Scale (ZSAS). Using the AF group as a reference, the control group consisted of randomly selected age- and sex-matched individuals in a 1:5 ratio (case:control = 1:5). The association between anxiety and AF in the AF group and the multifactor-matched control group was explored using logistic regression. Results In the AF and control groups, after adjusting for a history of coronary heart disease, valvular heart disease, hypertension, stroke, hyperlipidemia, and diabetes, as well as depression score, ZSAS scores (odds ratio 1.07; 95% confidence interval 1.02–1.12; p = 0.003), and anxiety symptoms (odds ratio 3.94; 95% confidence interval 1.06–14.70; p = 0.041) were associated with AF. Conclusions Anxiety symptoms were associated with AF in a Chinese older population. This suggests that older adults who have anxiety symptoms may need psychological intervention or treatment in daily life and care.

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Nested Case-Control Studies With Multiple Measurements: Estimating Marginal Relationships

10.21203/rs.3.rs-482695/v1 ◽

2021 ◽

Author(s):

Joshua N. Sampson ◽

Paul S. Albert ◽

Mark P. Purdue

Keyword(s):

Conditional Logistic Regression ◽

Case Control ◽

Case Control Studies ◽

Robust Variance ◽

Non Hodgkin Lymphoma ◽

Multiple Measurements ◽

Matched Case ◽

Nested Case Control ◽

Standard Software ◽

Single Time Point

Abstract Background: We consider the analysis of nested, matched, case-control studies that have multiple biomarker measurements per individual. We propose a simple approach for estimating the marginal relationship between a biomarker measured at a single time point and the risk of an event. We know of no other standard software package that can perform such analyses while explicitly accounting for the matching. Results: We propose an application of conditional logistic regression (CLR) that can include all measurements and uses a robust variance estimator. We compare our approach to other methods such as performing CLR with only the first measurement, CLR with an average of all measurements, and Generalized Estimating Equations. In simulations, our approach is significantly more powerful than CLR with one measurement or an average of all measurements, and has similar to power to GEE but correctly accounts for the matching. We then apply our approach to the CLUE cohort to show that an increased level of the immune marker sCD27 is associated with non‐Hodgkin lymphoma (NHL) and, by evaluating the strength of the association as a function of time until diagnosis, that the an increased level is likely an effect of the disease as opposed to a cause of the disease. The approach can be implemented by the R function clogitRV available at https://github.com/sampsonj74/clogitRV.Conclusion: We offered an approach and software for analyzing matched case-control studies with multiple measurements. We demonstrated that these methods are accurate, precise, and statistically powerful.

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Risk of osteoporosis and fragility fractures in asthma due to oral and inhaled corticosteroids: two population-based nested case-control studies

Thorax ◽

10.1136/thoraxjnl-2020-215664 ◽

2020 ◽

Vol 76 (1) ◽

pp. 21-28 ◽

Cited By ~ 1

Author(s):

Christos V Chalitsios ◽

Dominick E Shaw ◽

Tricia M McKeever

Keyword(s):

Cumulative Dose ◽

Inhaled Corticosteroids ◽

Conditional Logistic Regression ◽

Fragility Fractures ◽

Case Control ◽

Practice Research ◽

Clinical Practice Research Datalink ◽

Case Control Studies ◽

Increased Risk ◽

Nested Case Control

BackgroundInhaled (ICS) and oral (OCS) corticosteroids are used widely in asthma; however, the risk of osteoporosis and fragility fracture (FF) due to corticosteroids in asthma is not well-established.MethodsWe conducted two nested case-control studies using linked data from the Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) databases. Using an asthma cohort, we separately identified patients with osteoporosis or FF and gender-, age- and practice-matched controls. Conditional logistic regression was used to determine the association between ICS and OCS exposure, and the risk of osteoporosis or FF. The prevalence of patients receiving at least one bisphosphonate was also calculated.ResultsThere was a dose–response relationship between both cumulative dose and number of OCS/ICS prescriptions within the previous year, and risk of osteoporosis or FF. After adjusting for confounders, people receiving more OCS prescriptions (≥9 vs 0) had a 4.50 (95% CI 3.21 to 6.11) and 2.16 (95% CI 1.56 to 3.32) increased risk of osteoporosis and FF, respectively. For ICS (≥11 vs 0) the ORs were 1.60 (95% CI 1.22 to 2.10) and 1.31 (95% CI 1.02 to 1.68). The cumulative dose had a similar impact, with those receiving more OCS or ICS being at greater risk. The prevalence of patients taking ≥9 OCS and at least one bisphosphonate prescription was just 50.6% and 48.4% for osteoporosis and FF, respectively.ConclusionsThe findings suggest that exposure to OCS or ICS is an independent risk factors for bone health in patients with asthma. Steroid administration at the lowest possible level to maintain asthma control is recommended.

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The ‘well control’ artefact in case/control studies of specific psychiatric disorders

Psychological Medicine ◽

10.1017/s0033291700024338 ◽

1989 ◽

Vol 19 (3) ◽

pp. 737-742 ◽

Cited By ~ 23

Author(s):

Sharon Schwartz ◽

Bruce G. Link

Keyword(s):

Risk Factor ◽

Psychiatric Disorders ◽

Group Selection ◽

Case Control ◽

Control Group ◽

Case Control Studies ◽

Suggested Approach ◽

Well Control ◽

Risk Factor Assessment ◽

Intuitive Appeal

SynopsisAn appropriate choice of controls in case/control studies of specific psychiatric disorders is crucial for valid risk-factor assessment. One suggested approach to control-group selection, the use of a well control group, is the focus of this paper. While using well controls has intuitive appeal, this paper shows that such a procedure can lead to ambiguous and biased results.

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