Choosing questions before methods in dementia research with competing events and causal goals

Several of the hypothesized or studied exposures that may affect dementia risk are known to increase the risk of death. This may explain counterintuitive results, where exposures that are known to be harmful for mortality risk sometimes seem protective for the risk of dementia. Authors have attempted to explain these counterintuitive results as biased, but the bias associated with a particular analytic method cannot be defined or assessed if the causal question is not explicitly specified. Indeed, we can consider several causal questions when competing events like death, which cannot be prevented by design, are present. Current dementia research guidelines have not explicitly considered what constitutes a meaningful causal question in this setting or, more generally, how this choice justifies and should drive particular analytic decisions. To contextualize current practices, we first perform a systematic review of the conduct and interpretation of longitudinal studies focused on dementia outcomes where death is a competing event. We then describe and demonstrate how to address different causal questions (referred here as "the total effect" and "the controlled direct effect") with traditional analytic approaches under explicit assumptions. Our application focuses on smoking cessation in late-midlife. To illustrate core concepts, we discuss this example both in terms of a hypothetical randomized trial and with an emulation of such a trial using observational data from the Rotterdam Study.

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Looking at competing events through a different lens in dementia research: Examples from the Rotterdam Study

Alzheimer s & Dementia ◽

10.1002/alz.045204 ◽

2020 ◽

Vol 16 (S10) ◽

Author(s):

Liliana Paloma Rojas‐Saunero ◽

M Arfan Ikram ◽

Sonja Swanson

Keyword(s):

Rotterdam Study ◽

Dementia Research ◽

Competing Events

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Cardiac biomarkers in acute respiratory distress syndrome: a systematic review and meta-analysis

Journal of Intensive Care ◽

10.1186/s40560-021-00548-6 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Dilip Jayasimhan ◽

Simon Foster ◽

Catherina L. Chang ◽

Robert J. Hancox

Keyword(s):

Systematic Review ◽

Acute Respiratory Distress Syndrome ◽

Intensive Care ◽

Cardiac Dysfunction ◽

Distress Syndrome ◽

Troponin I ◽

Meta Analysis ◽

Cardiac Injury ◽

Cardiac Biomarkers ◽

Risk Of Death

Abstract Background Acute respiratory distress syndrome (ARDS) is a leading cause of morbidity and mortality in the intensive care unit. Biochemical markers of cardiac dysfunction are associated with high mortality in many respiratory conditions. The aim of this systematic review is to examine the link between elevated biomarkers of cardiac dysfunction in ARDS and mortality. Methods A systematic review of MEDLINE, EMBASE, Web of Science and CENTRAL databases was performed. We included studies of adult intensive care patients with ARDS that reported the risk of death in relation to a measured biomarker of cardiac dysfunction. The primary outcome of interest was mortality up to 60 days. A random-effects model was used for pooled estimates. Funnel-plot inspection was done to evaluate publication bias; Cochrane chi-square tests and I2 tests were used to assess heterogeneity. Results Twenty-two studies were included in the systematic review and 18 in the meta-analysis. Biomarkers of cardiac stretch included NT-ProBNP (nine studies) and BNP (six studies). Biomarkers of cardiac injury included Troponin-T (two studies), Troponin-I (one study) and High-Sensitivity-Troponin-I (three studies). Three studies assessed multiple cardiac biomarkers. High levels of NT-proBNP and BNP were associated with a higher risk of death up to 60 days (unadjusted OR 8.98; CI 4.15-19.43; p<0.00001). This association persisted after adjustment for age and illness severity. Biomarkers of cardiac injury were also associated with higher mortality, but this association was not statistically significant (unadjusted OR 2.21; CI 0.94-5.16; p= 0.07). Conclusion Biomarkers of cardiac stretch are associated with increased mortality in ARDS.

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Prevalence and Impact of Atrial Fibrillation in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm10112490 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2490

Author(s):

Giulio Francesco Romiti ◽

Bernadette Corica ◽

Gregory Y. H. Lip ◽

Marco Proietti

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Meta Analysis ◽

Geographical Location ◽

Treatment Strategies ◽

Cardiovascular Complications ◽

Risk Of Death ◽

All Cause Mortality ◽

High Degree ◽

Degree Of Heterogeneity

Background: In patients with COVID-19, cardiovascular complications are common and associated with poor prognosis. Among these, an association between atrial fibrillation (AF) and COVID-19 has been described; however, the extent of this relationship is unclear. The aim of this study is to investigate the epidemiology of AF in COVID-19 patients and its impact on all-cause mortality. Methods: A systematic review and meta-analysis were performed and reported according to PRISMA guidelines, and a protocol for this study was registered on PROSPERO (CRD42021227950). PubMed and EMBASE were systematically searched for relevant studies. A random-effects model was used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Results: Overall, 31 studies were included in the analysis, with a total number of 187,716 COVID-19 patients. The prevalence of AF was found to be as high as 8% of patients with COVID-19 (95% CI: 6.3–10.2%, 95% prediction intervals (PI): 2.0–27.1%), with a high degree of heterogeneity between studies; a multiple meta-regression model including geographical location, age, hypertension, and diabetes showed that these factors accounted for more than a third of the heterogeneity. AF COVID-19 patients were less likely to be female but more likely older, hypertensive, and with a critical status than those without AF. Patients with AF showed a significant increase in the risk of all-cause mortality (OR: 3.97, 95% CI: 2.76–5.71), with a high degree of heterogeneity. A sensitivity analysis focusing on new-onset AF showed the consistency of these results. Conclusions: Among COVID-19 patients, AF is found in 8% of patients. AF COVID-19 patients are older, more hypertensive, and more likely to have a critical status. In COVID-19 patients, AF is associated with a 4-fold higher risk of death. Further studies are needed to define the best treatment strategies to improve the prognosis of AF COVID-19 patients.

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Benzodiazepines and antipsychotic medications for treatment of acute cocaine toxicity in animal models – A systematic review and meta-analysis

Human & Experimental Toxicology ◽

10.1177/0960327111401435 ◽

2011 ◽

Vol 30 (11) ◽

pp. 1849-1854 ◽

Cited By ~ 13

Author(s):

Kennon Heard ◽

Nathan R Cleveland ◽

Shay Krier

Keyword(s):

Systematic Review ◽

Animal Models ◽

Antipsychotic Medication ◽

English Language ◽

Absolute Risk ◽

Meta Analysis ◽

Absolute Risk Reduction ◽

Antipsychotic Medications ◽

Risk Of Death ◽

Cocaine Toxicity

There are no controlled human studies to determine the efficacy of benzodiazepines or antipsychotic medications for prevention or treatment of acute cocaine toxicity. The only available controlled data are from animal models and these studies have reported inconsistent benefits. The objective of this study was to quantify the reported efficacy of benzodiazepines and antipsychotic medication for the prevention of mortality due to cocaine poisoning. We conducted a systematic review to identify English language articles describing experiments that compared a benzodiazepine or antipsychotic medication to placebo for the prevention of acute cocaine toxicity in an animal model. We then used these articles in a meta-analysis with a random-effects model to quantify the absolute risk reduction observed in these experiments. We found 10 articles evaluating antipsychotic medications and 15 articles evaluating benzodiazepines. Antipsychotic medications reduced the risk of death by 27% (95% CI, 15.2%–38.7%) compared to placebo and benzodiazepines reduced the risk of death by 52% (42.8%–60.7%) compared to placebo. Both treatments showed evidence of a dose-response effect, and no experiment found a statistically significant increase in risk of death. We conclude that both benzodiazepines and antipsychotic medications are effective for the prevention of lethality from cocaine toxicity in animal models.

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The Effect of Anakinra in Hospitalized Patients with COVID-19: An Updated Systematic Review and Meta-Analysis

Journal of Clinical Medicine ◽

10.3390/jcm10194462 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4462

Author(s):

Konstantinos G. Kyriakoulis ◽

Anastasios Kollias ◽

Garyphallia Poulakou ◽

Ioannis G. Kyriakoulis ◽

Ioannis P. Trontzas ◽

...

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Interleukin 1 ◽

Severe Pneumonia ◽

Hospitalized Patients ◽

Current Evidence ◽

Adjusted Risk ◽

Risk Of Death ◽

The Impact

The role of immunomodulatory agents in the treatment of hospitalized patients with COVID-19 has been of increasing interest. Anakinra, an interleukin-1 inhibitor, has been shown to offer significant clinical benefits in patients with COVID-19 and hyperinflammation. An updated systematic review and meta-analysis regarding the impact of anakinra on the outcomes of hospitalized patients with COVID-19 was conducted. Studies, randomized or non-randomized with adjustment for confounders, reporting on the adjusted risk of death in patients treated with anakinra versus those not treated with anakinra were deemed eligible. A search was performed in PubMed/EMBASE databases, as well as in relevant websites, until 1 August 2021. The meta-analysis of six studies that fulfilled the inclusion criteria (n = 1553 patients with moderate to severe pneumonia, weighted age 64 years, men 66%, treated with anakinra 50%, intubated 3%) showed a pooled hazard ratio for death in patients treated with anakinra at 0.47 (95% confidence intervals 0.34, 0.65). A meta-regression analysis did not reveal any significant associations between the mean age, percentage of males, mean baseline C-reactive protein levels, mean time of administration since symptoms onset among the included studies and the hazard ratios for death. All studies were considered as low risk of bias. The current evidence, although derived mainly from observational studies, supports a beneficial role of anakinra in the treatment of selected patients with COVID-19.

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Convalescent Plasma Therapy in Severe and Critically Ill COVID-19 Patients: A Systematic Review and Meta-Analysis

10.21203/rs.3.rs-876454/v1 ◽

2021 ◽

Author(s):

Penglei Yang ◽

Jing Wang ◽

Ruiqiang Zheng ◽

Rui Tan ◽

Xianghui Li ◽

...

Keyword(s):

Systematic Review ◽

Critically Ill ◽

Virus Disease ◽

Therapy Group ◽

Meta Analysis ◽

Control Group ◽

Plasma Therapy ◽

Risk Of Death ◽

Randomized Controlled ◽

Randomized Controlled Studies

Abstract Background: Convalescent plasma treatment of severe and critically ill Corona Virus Disease 2019(COVID-19) patients is still controversial.Objective: To evaluate the efficacy and safety of convalescent plasma in patients with severe COVID-19 infection and critically ill patients, We performed a meta-analysis and systematic review of convalescent plasma therapy in severe and critically ill COVID-19 patients.Methods: We conducted a literature search in electronic data and citations of previously published systematic reviews. We included only randomized controlled studies on convalescent plasma for the treatment of severe and critically ill COVID-19 patients. Results: A total of 7 randomized controlled trials and 1363 patients were included in the meta-analysis. Compared to patients of the control group, there was no difference in clinical improvement (Four studies, RR 1.06, 95% CI 0.96 to 1.17, p = 0.22, moderate certainty) and mortality (seven studies, RR 0.86, 95% CI 0.66 to 1.11, p = 0.48, moderate certainty) for patients of convalescent plasma therapy group.Conclusion: Convalescent plasma does not reduce the improvement of symptoms and the risk of death in severely infected and critically ill COVID-19 patients

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Predictive Performance of Serum S100B Versus LDH in Melanoma Patients: A Systematic Review and Meta-Analysis

Frontiers in Oncology ◽

10.3389/fonc.2021.772165 ◽

2021 ◽

Vol 11 ◽

Author(s):

Eszter Anna Janka ◽

Tünde Várvölgyi ◽

Zoltán Sipos ◽

Alexandra Soós ◽

Péter Hegyi ◽

...

Keyword(s):

Systematic Review ◽

Study Protocol ◽

Systematic Reviews ◽

Meta Analysis ◽

Elevated Serum ◽

Predictive Performance ◽

Discriminative Ability ◽

Serum S100b ◽

Risk Of Death ◽

Melanoma Patients

BackgroundCurrently, no consensus on the use of blood tests for monitoring disease recurrence in patients with resected melanoma exists. The only meta-analysis conducted in 2008 found that elevated serum S100B levels were associated with significantly worse survival in melanoma patients. Serum LDH is an established prognostic factor in patients with advanced melanoma.ObjectiveTo compare the discriminative and prognostic ability of serum S100B with that of serum LDH in patients with melanoma.MethodsThis systematic review and meta-analysis were reported in accordance with the PRISMA Statement. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138).ResultsA quantitative analysis of data from 6 eligible studies included 1,033 patients with cutaneous melanoma. The discriminative ability of serum S100B at identifying disease relapse [pooled Area Under the ROC (AUROC) 78.64 (95% CI 70.28; 87.01)] was significantly greater than the discriminative ability of serum LDH [AUROC 64.41 (95% CI 56.05; 7278)] (p=0.013). Ten eligible studies with 1,987 patients were included in the risk of death analysis. The prognostic performance of serum S100B [pooled estimate of adjusted hazard ratio (HR) 1.78 (95% CI 1.38; 2.29)] was independent but not superior to that of serum LDH [HR 1.60 (95% CI 1.36; 2.29)].LimitationsA relatively small number of articles were eligible and there was considerable heterogeneity across the included studies.ConclusionsSerum biomarkers may provide relevant information on melanoma patient status and should be further researched. Serum S100B is a valid marker for diagnosis of melanoma recurrence.Systematic Review RegistrationThe study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019137138).

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Does apolipoprotein E genotype moderate the association between physical activity and brain health? A systematic review and meta-analysis

10.31234/osf.io/gkpbz ◽

2021 ◽

Author(s):

Andrew Mark Pearce ◽

Calum Marr ◽

Michaela Dewar ◽

Alan J. Gow

Keyword(s):

Physical Activity ◽

Systematic Review ◽

Apolipoprotein E ◽

Meta Analysis ◽

Brain Activation ◽

Brain Health ◽

Compensatory Mechanisms ◽

Dementia Risk ◽

E4 Allele ◽

Post Hoc

Introduction: Possession of one or two e4 alleles of the apolipoprotein E (APOE) gene is associated with cognitive decline and dementia risk. Some evidence suggests that physical activity may benefit carriers of the e4 allele differently.Method: We conducted a systematic review and meta-analysis of studies which assessed APOE differences in the association between physical activity and: lipid profile, Alzheimer’s disease pathology, brain structure and brain function in healthy adults. Searches were carried out in PubMed, SCOPUS, Web of Science and PsycInfo.Results: Thirty studies were included from 4896 papers screened. Carriers of the e4 allele gained the same benefit from physical activity as non-carriers on most outcomes. For brain activation, e4 carriers appeared to gain a greater benefit from physical activity in activation and functional connectivity compared to non-carriers. Post hoc analysis identified possible compensatory mechanisms allowing e4 carriers to maintain cognitive function.Discussion: Though there is evidence suggesting physical activity may benefit e4 carriers differently compared to non-carriers, this may vary by the specific brain health outcome, perhaps limited to brain activation. Further research is required to confirm these findings and elucidate the mechanisms.

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