Adjustment for collider bias in the hospitalized Covid-19 setting.

Background: Causal directed acyclic graphs (cDAGs) are frequently used to identify confounding and collider bias. We demonstrate how to use causal directed acyclic graphs to adjust for collider bias in the hospitalized Covid-19 setting. Materials and methods: According to the cDAGs, three types of modeling have been performed. In model 1, only vaccination is entered as an independent variable. In model 2, in addition to vaccination, age is entered the model to adjust for collider bias due to the conditioning of hospitalization. In model 3, comorbidities are also included for adjustment of collider bias due to the conditioning of hospitalization in different biasing paths intercepting age and comorbidities. Results: There was no evidence of the effect of vaccination on preventing death due to Covid-19 in model 1. In the second model, where age was included as a covariate, a protective role for vaccination became evident. In model 3, after including chronic diseases as other covariates, the protective effect was slightly strengthened. Conclusion: Studying hospitalized patients is subject to collider-stratification bias. Like confounding, this type of selection bias can be adjusted for by inclusion of the risk factors of the outcome which also affect hospitalization in the regression model.

The effect of smoking on latent hazard classes of metabolic syndrome using latent class causal analysis method in the Iranian population.

BACKGROUND: The prevalence of metabolic syndrome is increasing worldwide. Clinical guidelines consider metabolic syndrome as an all or none medical condition. One proposed method for classifying metabolic syndrome is latent class analysis (LCA). One approach to causal inference in LCA is using propensity score (PS) methods. The aim of this study was to investigate the causal effect of smoking on latent hazard classes of metabolic syndrome using the method of latent class causal analysis. METHODS: In this study, we used data from the Tehran Lipid and Glucose Cohort Study (TLGS). 4857 participants aged over 20 years with complete information on exposure (smoking) and confounders in the third phase (2005-2008) were included. Metabolic syndrome was evaluated as outcome and latent variable in LCA in the data of the fifth phase (2014-2015). The step-by-step procedure for conducting causal inference in LCA included: (1) PS estimation and evaluation of overlap, (2) calculation of inverse probability-of-treatment weighting (IPTW), (3) PS matching, (4) evaluating balance of confounding variables between exposure groups, and (5) conducting LCA using the weighted or matched data set. RESULTS: Based on the results of IPTW which compared the low, medium and high risk classes of metabolic syndrome (compared to a class without metabolic syndrome), no association was found between smoking and the metabolic syndrome latent classes. PS matching which compared low and moderate risk classes compared to class without metabolic syndrome, showed that smoking increases the probability of being in the low-risk class of metabolic syndrome (OR: 2.19; 95% CI: 1.32, 3.63). In the unadjusted analysis, smoking increased the chances of being in the low-risk (OR: 1.45; 95% CI: 1.01, 2.08) and moderate-risk (OR: 1.68; 95% CI: 1.18, 2.40) classes of metabolic syndrome compared to the class without metabolic syndrome. CONCLUSIONS: Based on the results, the causal effect of smoking on latent hazard classes of metabolic syndrome can be different based on the type of PS method. In adjusted analysis, no relationship was observed between smoking and moderate-risk and high-risk classes of metabolic syndrome.

Prevention of Re-attempt Suicide Through Brief Contact Interventions: A Systematic Review, Meta-analysis, and Meta-regression of Randomized Controlled Trials.

Brief contact intervention (BCI) is a low-cost intervention to prevent re-attempt suicide. This meta-analysis and meta-regression study aimed to evaluate the effect of BCI on re-attempt prevention following suicide attempts (SAs). We systematically searched using defined keywords in MEDLINE, Embase, and Scopus up to April, 2023. All randomized controlled trials (RCTs) were eligible for inclusion after quality assessment. Random-effects model and subgroup analysis were used to estimate pooled risk difference (RD) and risk ratio (RR) between BCI and re-attempt prevention with 95% confidence intervals (CIs). Meta-regression analysis was carried out to explore the potential sources of heterogeneity. The pooled estimates were (RD = 4%; 95% CI 2-6%); and (RR = 0.62; 95% CI 0.48-0.77). Subgroup analysis demonstrated that more than 12 months intervention (RR = 0.46; 95% CI 0.10-0.82) versus 12 months or less (RR = 0.67; 95% CI 0.54-0.80) increased the effectiveness of BCI on re-attempt suicide reduction. Meta-regression analysis explored that BCI time (more than 12 months), BCI type, age, and female sex were the potential sources of the heterogeneity. The meta-analysis indicated that BCI could be a valuable strategy to prevent suicide re-attempts. BCI could be utilized within suicide prevention strategies as a surveillance component of mental health since BCI requires low-cost and low-educated healthcare providers.

Comparison of corticosteroids types, dexamethasone, and methylprednisolone in patients hospitalized with COVID-19: A systematic review and network meta-analysis.

Background: COVID-19 is associated with severe pneumonia lung damage, acute respiratory distress syndrome (ARDS), and mortality. In this study, we aimed to compare corticosteroids' effect on the mortality risk in patients hospitalized with COVID-19. Methods: PubMed, Web of Science, Scopus, Cochrane Library, and Embase, were searched using a predesigned search strategy. Randomized controlled trials (RCTs) that had compared the corticosteroid drugs were included. The hazard ratio (HR) with a 95% confidence interval (CI) was used to summarize the effect size from the network meta-analysis (NMA). Results: Out of 329 retrieved references, 12 RCTs with 11,455 participants met the eligibility criteria in this review. The included RCTs formed one network with six treatments. In addition, five treatments in two RCTs were not connected to the network. Methylprednisolone + usual care (UC) versus UC decreased the risk of death by 0.65 (95% CI: 0.47, 0.90). Among treatments in the network the highest P-score (0.89) was related to Methylprednisolone + UC. Conclusion: Based on the results of this NMA it seems Methylprednisolone + UC to be the best treatment option in patients with COVID-ARDS and COVID pneumonia.

Effect of alcohol consumption on breast cancer: probabilistic bias analysis for adjustment of exposure misclassification bias and confounders.

PURPOSE: This study was conducted to evaluate the effect of alcohol consumption on breast cancer, adjusting for alcohol consumption misclassification bias and confounders. METHODS: This was a case-control study of 932 women with breast cancer and 1000 healthy control. Using probabilistic bias analysis method, the association between alcohol consumption and breast cancer was adjusted for the misclassification bias of alcohol consumption as well as a minimally sufficient set of adjustment of confounders derived from a causal directed acyclic graph. Population attributable fraction was estimated using the Miettinen's Formula. RESULTS: Based on the conventional logistic regression model, the odds ratio estimate between alcohol consumption and breast cancer was 1.05 (95% CI: 0.57, 1.91). However, the adjusted estimates of odds ratio based on the probabilistic bias analysis ranged from 1.82 to 2.29 for non-differential and from 1.93 to 5.67 for differential misclassification. Population attributable fraction ranged from 1.51 to 2.57% using non-differential bias analysis and 1.54-3.56% based on differential bias analysis. CONCLUSION: A marked measurement error was in self-reported alcohol consumption so after correcting misclassification bias, no evidence against independence between alcohol consumption and breast cancer changed to a substantial positive association.

Protective effect of intensive glucose lowering therapy on all-cause mortality, adjusted for treatment switching using G-estimation method, the ACCORD trial.

Previous analysis of the action to control cardiovascular risk in diabetes showed an increased risk of mortality among patients receiving intensive glucose lowering therapy using conventional regression method with intention to treat approach. This method is biased when time-varying confounder is affected by the previous treatment. We used 15 follow-up visits of ACCORD trial to compare the effect of time-varying intensive vs. standard treatment of glucose lowering drugs on cardiovascular and mortality outcomes in diabetic patients. The treatment effect was estimated using G-estimation and compared with accelerated failure time model using two modeling strategies. The first model adjusted for baseline confounders and the second adjusted for both baseline and time-varying confounders. While the hazard ratio of all-cause mortality for intensive compared to standard therapy in AFT model adjusted for baseline confounders was 1.17 (95% CI 1.01-1.36), the result of time-dependent AFT model  was compatible with both protective and risk effects. However, the hazard ratio estimated by G-estimation was 0.64 (95% CI 0.39-0.92). The results of this study revealed a protective effect of intensive therapy on all-cause mortality compared with standard therapy in ACCORD trial.

Additive interaction between dietary inflammatory index and some key risk factors of multiple sclerosis: a population-based incident case-control study.

BACKGROUND: Recently, dietary inflammatory index (DII) has been introduced as a significant risk factor for MS. We examined the interaction between dietary inflammatory index and some formerly demonstrated key risk factors of multiple sclerosis (MS). MATERIAL AND METHODS: We conducted a population-based incident case-control study of 547 MS cases and 1057 controls. Multiplicative and additive interaction were assessed using interaction term in the logistic regression model and synergy index (SI), respectively. RESULTS: Additive interaction was detected between DII and drug abuse (SI = 2.58; 95% CI: 1.14-5.82), gender (SI = 2.00; 95% CI: 1.39-2.87) and history of depression (SI = 1.68; 95% CI: 1.04-2.72) on the risk scale. The risk of MS in drug abusers with DII ≥ 0 was 10.4-times higher than that in non-drug abusers with DII < 0 (OR = 10.4, 95% CI: 5.12-21.02, P < 0.001). We also found that women with DII ≥ 0 had a 9.2 times larger risk compared with the men with DII < 0(OR = 9.2, 95% CI: 6.3-13.5, P < 0.001). Similarly, the risk of MS was remarkably higher in those with a history of depression and DII >0 (OR = 7.6, 95% CI: 5.1-11.5, P < 0.001). There was no evidence of multiplicative interaction between DII and the other risk factors of MS on the risk scale. CONCLUSIONS: We identified additive interaction between DII and drug abuse, gender and history of depression on MS. Further studies are needed to understand the underlying mechanisms of these detected interactions.

Plant-based diet and COVID-19 severity: results from a cross-sectional study.

Although previous findings have shown the beneficial role of healthy eating pattern on the human immune system, the association between plant-based diet and COVID-19 severity has not yet been elucidated. This study aimed to determine the possible role of plant-based diet index (PDI) in COVID-19 severity. This cross-sectional, multicentral study was conducted on 141 patients with confirmed COVID-19. Dietary intakes of the patients were evaluated using a validated food frequency questionnaire. Then, PDI was compared between patients who needed to be hospitalised (considered severe cases), and those who got treatment at home (considered non-severe cases). After adjustment for confounders including age, sex, energy intake and body mass index, lower odds of hospitalisation were found for participants having a greater score of overall PDI (OR per 10 units increase: 0.42; 95% CI 0.22 to 0.80) and healthy PDI (OR per 10 unit increase: 0.45; 95% CI 0.26 to 0.78). In conclusion, our data presented that there is a relation between PDI and lower risk of hospitalisation in COVID-19 patients, possibly through boosting the immune function.

Impact of Alcohol Consumption on Multiple Sclerosis Using Model-based Standardization and Misclassification Adjustment Via Probabilistic Bias Analysis.

BACKGROUND: The etiology of multiple sclerosis (MS) is still not well-demonstrated, and assessment of some risk factors like alcohol consumption has problems like confounding and measurement bias. To determine the causal effect of alcohol consumption on MS after adjusting for alcohol consumption misclassification bias and confounders. METHODS: In a population-based incident case-control study, 547 patients with MS and 1057 healthy people were recruited. A minimally sufficient adjustment set of confounders was derived using the causal directed acyclic graph. The probabilistic bias analysis method (PBAM) using beta, logit-logistic, and triangular probability distributions for sensitivity/specificity to adjust for misclassification bias in self-reporting alcohol consumption and model-based standardization (MBS) to estimate the causal effect of alcohol consumption were used. Population attributable fraction (PAF) estimates with 95% Monte Carlo sensitivity analysis (MCSA) intervals were calculated using PBAM and MBS analysis. Bootstrap was used to deal with random errors. RESULTS: The adjusted risk ratio (95% MCSA interval) from the probabilistic bias analysis and MBS between alcohol consumption and MS using the three distribution was in the range of 1.93 (1.07 to 4.07) to 2.02 (1.15 to 4.69). The risk difference (RD) in all three scenarios was 0.0001 (0.0000 to 0.0005) and PAF was in the range of 0.15 (0.010 to 0.50) to 0.17 (0.001 to 0.47). CONCLUSION: After adjusting for measurement bias, confounding, and random error alcohol consumption had a positive causal effect on the incidence of MS.

Development and validation of an online tool for assessment of health care providers' management of suspected malaria in an area, where transmission has been interrupted.

BACKGROUND: The alertness and practice of health care providers (HCPs) in the correct management of suspected malaria (CMSM) (vigilance) is a central component of malaria surveillance following elimination, and it must be established before malaria elimination certification can be granted. This study was designed to develop and validate a rapid tool, Simulated Malaria Online Tool (SMOT), to evaluate HCPs' practice in relation to the CMSM. METHODS: The study was conducted in East Azerbaijan Province, Islamic Republic of Iran, where no malaria transmission has been reported since 2005. An online tool presenting a suspected malaria case for detection of HCPs' failures in recognition, diagnosis, treatment and reporting was developed based on literature review and expert opinion. A total of 360 HCPs were allocated to two groups. In one group their performance was tested by simulated patient (SP) methodology as gold standard, and one month later by the online tool to allow assessment of its sensitivity. In the other group, they were tested only by the online tool to allow assessment of any possible bias incurred by the exposure to SPs before the tool. RESULTS: The sensitivity of the tool was (98.7%; CI 93.6-99.3). The overall agreement and kappa statistics were 96.6% and 85.6%, respectively. In the group tested by both methods, the failure proportion by SP was 86.1% (CI 80.1-90.8) and by tool 87.2% (CI 81.4-91.7). In the other group, the tool found 85.6% (CI 79.5-90.3) failures. There were no significant differences in detecting failures within or between the groups. CONCLUSION: The SMOT tool not only showed high validity for detecting HCPs' failures in relation to CMSM, but it had high rates of agreement with the real-world situation, where malaria transmission has been interrupted. The tool can be used by program managers to evaluate HCPs' performance and identify sub-groups, whose malaria vigilance should be strengthened. It could also contribute to the evidence base for certification of malaria elimination, and to strengthening prevention of re-establishment of malaria transmission.

Validity and reliability of the persian version of the world health organization quality of life disabilities module.

This study aimed to assess the validity and reliability of the world health organization quality of life questionnaire for people with intellectual disability (WHOQOL-DIS-ID). This was a cross-sectional study of 118 adults with intellectual disability. Internal consistency and temporal reliability were evaluated using Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Construct validity of the structure was assessed using confirmatory factor analysis. Multiple linear regression analysis was performed to determine the factors associated with the quality of life. Cronbach's alpha for all, but not for discrimination area, as well as ICC for all questions except for 23 and 6, were higher than 0.7. The variables such as periodic check-up, number of friends, entertainment outside the home, parental separation, physical activity, unmet needs score, caregiver's mental health status, and available facilities were the predictors of QOL. The Persian version of the WHOQOL-DIS-ID shows acceptable validity and reliability.

Serum lysyl oxidase concentration increases in long-standing systemic sclerosis: Can lysyl oxidase change over time?

Objectives: This study aims to investigate the association of serum lysyl oxidase (LOX) levels with systemic sclerosis (SSc), to examine the relationship between LOX and disease onset, and to evaluate the probable effects of hyperlipidemia on the circulating levels of LOX among patients with SSc. Patients and methods: Between May 2017 and November 2018, a total of 39 patients with SSc (2 males, 37 females; mean age: 46.6±12.3 years; range, 18 to 65 years) and 35 healthy controls (4 males, 31 females; mean age: 43.1±14.1 years; range, 18 to 65 years) were included. Serum LOX concentration was measured using the enzyme-linked immunoassay in triplicate. Results: We found higher levels of serum LOX in patients with SSc compared to healthy controls. There was a significant relationship between serum LOX levels and disease onset. Patients with long-standing disease demonstrated increased levels of LOX in the blood compared to the recent-onset group. Hyperlipidemia did not have a significant effect on circulating levels of LOX. There was a significant negative correlation between LOX levels and modified Rodnan Skin Score in the subgroup of patients with skin involvement only and in patients without gastrointestinal involvement. Conclusion: Our study findings show an increased level of LOX protein level in the blood of patients diagnosed with SSc. Hyperlipidemia seems not to affect the concentrations of LOX in the peripheral blood of patients with SSc.

Longitudinal causal effect of modified creatinine index on all-cause mortality in patients with end-stage renal disease: Accounting for time-varying confounders using G-estimation.

BACKGROUND: Standard regression modeling may cause biased effect estimates in the presence of time-varying confounders affected by prior exposure. This study aimed to quantify the relationship between declining in modified creatinine index (MCI), as a surrogate marker of lean body mass, and mortality among end stage renal disease (ESRD) patients using G-estimation accounting appropriately for time-varying confounders. METHODS: A retrospective cohort of all registered ESRD patients (n = 553) was constructed over 8 years from 2011 to 2019, from 3 hemodialysis centers at Kerman, southeast of Iran. According to changes in MCI, patients were dichotomized to either the decline group or no-decline group. Subsequently the effect of interest was estimated using G-estimation and compared with accelerated failure time (AFT) Weibull models using two modelling strategies. RESULTS: Standard models demonstrated survival time ratios of 0.91 (95% confidence interval [95% CI]: 0.64 to 1.28) and 0.84 (95% CI: 0.58 to 1.23) in patients in the decline MCI group compared to those in no-decline MCI group. This effect was demonstrated to be 0.57 (-95% CI: 0.21 to 0.81) using G-estimation. CONCLUSION: Declining in MCI increases mortality in patients with ESRD using G-estimation, while the AFT standard models yield biased effect estimate toward the null.

Does motor control training improve pain and function in adults with symptomatic lumbar disc herniation? A systematic review and meta-analysis of 861 subjects in 16 trials.

OBJECTIVE: To evaluate the effectiveness of motor control training (MCT) compared with other physical therapist-led interventions, minimal/no intervention or surgery in patients with symptomatic lumbar disc herniation (LDH). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Eight databases and the ClinicalTrials.gov were searched from inception to April 2021. ELIGIBILITY CRITERIA: We included clinical trial studies with concurrent comparison groups which examined the effectiveness of MCT in patients with symptomatic LDH. Primary outcomes were pain intensity and functional status which were expressed as mean difference (MD) and standardised mean difference (SMD), respectively. RESULTS: We screened 6695 articles, of which 16 clinical trials (861 participants) were eligible. Fourteen studies were judged to have high risk of bias and two studies had some risk of bias. In patients who did not undergo surgery, MCT resulted in clinically meaningful pain reduction compared with other physical therapist-led interventions (ie, transcutaneous electrical nerve stimulation (TENS)) at short-term (MD -28.85, -40.04 to -17.66, n=69, studies=2). However, the robustness of the finding was poor. For functional status, a large and statistically significant treatment effect was found in favour of MCT compared with traditional/classic general exercises at long-term (SMD -0.83 to -1.35 to -0.31, n=63, studies=1) and other physical therapist-led interventions (ie, TENS) at short-term (SMD -1.43 to -2.41 to -0.46, n=69, studies=2). No studies compared MCT with surgery. In patients who had undergone surgery, large SMDs were seen. In favour of MCT compared with traditional/classic general exercises (SMD -0.95 to -1.32 to -0.58, n=124, studies=3), other physical therapist-led interventions (ie, conventional treatments; SMD -2.30 to -2.96 to -1.64, n=60, studies=1), and minimal intervention (SMD -1.34 to -1.87 to -0.81, n=68, studies=2) for functional improvement at short-term. The overall certainty of evidence was very low to low. CONCLUSION: At short-term, MCT improved pain and function compared with TENS in patients with symptomatic LDH who did not have surgery. MCT improved function compared with traditional/classic general exercises at long-term in patients who had undergone surgery. However, the results should be interpreted with caution because of the high risk of bias in the majority of studies. PROSPERO REGISTRATION NUMBER: CRD42016038166.

Interaction Contrasts and Collider Bias.

Previous papers have mentioned that conditioning on a binary collider would introduce an association between its causes in at least 1 stratum. In this paper, we prove this statement and, along with intuitions, formally examine the direction and magnitude of the associations between 2 risk factors of a binary collider using interaction contrasts. Among level one of the collider, 2 variables are independent, positively associated, and negatively associated if multiplicative risk interaction contrast is equal to, more than, and less than 0, respectively; the same results hold for the other level of the collider if the multiplicative survival interaction contrast, equal to multiplicative risk interaction contrast minus the additive risk interaction contrast, is compared with 0. The strength of the association depends on the magnitude of the interaction contrast: The stronger the interaction is, the larger the magnitude of the association will be. However, the common conditional odds ratio under the homogeneity assumption will be bounded. A figure is presented that succinctly illustrates our results and helps researchers to better visualize the associations introduced upon conditioning on a collider.

Does weight mediate the effect of smoking on coronary heart disease? Parametric mediational g-formula analysis.

BACKGROUND: In settings in which there are time-varying confounders affected by previous exposure and a time-varying mediator, natural direct and indirect effects cannot generally be estimated unbiasedly. In the present study, we estimate interventional direct effect and interventional indirect effect of cigarette smoking as a time-varying exposure on coronary heart disease while considering body weight as a time-varying mediator. METHODS: To address this problem, the parametric mediational g-formula was proposed to estimate interventional direct effect and interventional indirect effect. We used data from the Multi-Ethnic Study of Atherosclerosis to estimate effect of cigarette smoking on coronary heart disease, considering body weight as time-varying mediator. RESULTS: Over a 11-years period, smoking 20 cigarettes per day compared to no smoking directly (not through weight) increased risk of coronary heart disease by an absolute difference of 1.91% (95% CI: 0.49%, 4.14%), and indirectly decreased coronary heart disease risk by -0.02% (95% CI: -0.05%, 0.04%) via change in weight. The total effect was estimated as an absolute 1.89% increase (95% CI: 0.49%, 4.13%). CONCLUSION: The overall absolute impact of smoking to incident coronary heart disease is modest, and we did not discern any important contribution to this effect relayed through changes to bodyweight. In fact, changes in weight because of smoking have no meaningful mediating effect on CHD risk.

P-value, compatibility, and S-value.

Misinterpretations of P-values and 95% confidence intervals are ubiquitous in medical research. Specifically, the terms significance or confidence, extensively used in medical papers, ignore biases and violations of statistical assumptions and hence should be called overconfidence terms. In this paper, we present the compatibility view of P-values and confidence intervals; the P-value is interpreted as an index of compatibility between data and the model, including the test hypothesis and background assumptions, whereas a confidence interval is interpreted as the range of parameter values that are compatible with the data under background assumptions. We also suggest the use of a surprisal measure, often referred to as the S-value, a novel metric that transforms the P-value, for gauging compatibility in terms of an intuitive experiment of coin tossing.

A practical guide to handling competing events in etiologic time-to-event studies.

Competing events are events that preclude the occurrence of the primary outcome. Much has been written on mainly the statistics behind competing events analyses. However, many of these publications and tutorials have a strong statistical tone and might fall short in providing a practical guide to clinician researchers as to when to use a competing event analysis and more importantly which method to use and why. Here we discuss the different target effects in the Fine-Gray and cause-specific methods using simple causal diagrams and provide strengths and limitations of both approaches for addressing etiologic questions. We argue why the Fine-Gray method might not be the best approach for handling competing events in etiological time-to-event studies.