Exposure-outcome Associations Research Articles

Assessment of postoperative therapy de-escalation for early-stage, intermediate-risk cervical cancer

ObjectiveThe objective of this study was to assess the oncologic outcome of surgically-treated patients with early-stage, intermediate-risk cervical cancer according to postoperative therapy modality.MethodsThis retrospective cohort study queried the Japanese...

How strong is the evidence supporting the WHO guidelines on physical activity, sedentary behaviour and sleep in early childhood?

The WHO issued recommendations about the ideal amount of physical activity, sedentary behaviour and sleep in infants, toddlers and preschool children. To facilitate their interpretation and translation into public health policies, we analysed the quantity and quality of the evidence that supported the development of each WHO recommendation. All data for each exposure-outcome pair analysed in the studies informing WHO guidelines were extracted, and predefined criteria, based upon GRADE methodology, were used to classify each outcome and study result. Among the 237 studies that could be included, 37 were experimental and 200 were observational, yielding 920 analyses of exposure-outcome associations. Sixty-two analyses used a relevant outcome, with or without significant results. Five of the 10 WHO recommendations were based upon zero analyses with significant results on relevant health outcomes. The remaining recommendations were mostly based upon analyses evaluating obesity-related outcomes. Eight of the 10 GLs thresholds were not supported by any significant analysis on clinically relevant outcomes. While these findings should not be interpreted as an attempt to disprove the benefits of healthy lifestyle habits in early childhood, neither to minimize the work of the experts in this complex research field, very limited evidence currently supports the adoption of recommended thresholds as behavioural surveillance and public health interventions targets. Therefore, until further data are available, public health interventions should be developed balancing whether to focus on the achievement of specific targets that are still not supported by high-quality evidence or on the general promotion of healthy behaviours.

Adjusting for covariates representing potential confounders, mediators, or competing predictors in the presence of measurement error: Dispelling a potential misapprehension and insights for optimal study design with nutritional epidemiology examples

Background Variables such as dietary intake are measured with error yet frequently used in observational epidemiology. Although this limitation is sometimes noted, these variables are still often modeled as covariates without formal correction or sincere dialogue about measurement unreliability potentially weakening the validity of statistical conclusions. Further, larger sample sizes increase power (bias) to detect spurious correlations. Counterintuitively, recent work suggested a non-monotonic relationship between confounder unreliability and how much controlling for the confounder reduces (or induces) bias when testing for an exposure-outcome association. If true, such non-monotonicity would be especially concerning for applications such as nutrition, where measurement reliability varies substantially, and large sample sizes are common. Methods We offer a detailed derivations of the square partial correlation between the outcome and exposure, controlling for the confounder. In our derivation, the measurement reliabilities of exposures and confounders are not arbitrarily constrained to be equal. Further, our theoretical results are investigated using simulations. Results Reassuringly, these derivations and simulations show that the counterintuitive non-monotonicity relationship between confounder unreliability and how much controlling for the confounder reduces (or induces) bias when testing for an exposure-outcome association is an artifact of the arbitrary constraint which forces the measurement reliabilities of exposures and confounders to be equal, which that does not always hold. Conclusions The profound and manifold effects of measurement error on estimation and statistical conclusion validity in realistic scenarios indicate that merely mentioning measurement error as a limitation and then dispensing with it is not an adequate response. We also explore questions for optimal study design subject to resource constraints when considering reliability of exposures, covariates, and outcomes.

Personality traits and co-occurrence of depressive symptoms and high BMI: a prospective cohort study.

We assess the associations between personality traits and co-occurrence of depressive symptoms and high BMI from adolescence to early adulthood. We employed a nationally representative cohort in China from 2010 to 2020 year. We included adolescents aged 10-19 years without depressive symptoms and unhealthy weight status (obesity, overweight, or thinness) at baseline and excluded those without any measurement of depressive symptoms or BMI at follow-ups. We assessed baseline personality traits in 7 dimensions of conscientiousness, openness, neuroticism, agreeableness, extraversion, self-esteem, and responsibility. We also assessed the combined effects of these 7 dimensions of personality traits by generating individual-level personality trait risk scores based on the weighted sum of all these 7 dimensions of personality traits. We measured the co-occurrence of depressive symptoms and high BMI using both a single measurement of depressive symptoms and BMI at the last follow-up and repeated measurements of them over 10 years. We used the multinomial logistic regression models to examine the exposure-outcome associations. At baseline, we included 1778 individuals (mean age: 14.4 year; female: 853 (48.0%)). At follow-ups, we observed increased risk of co-occurrence of depressive symptoms and high BMI per 1-SD increase in neuroticism score (1.95-2.38 odds ratio) or 1-SD decrease in self-esteem and conscientiousness (0.63-0.80 odds ratio; all P values < 0.05); we observed no evidence of associations between openness, agreeableness, extraversion, or responsibility and the risk of co-occurrence of depressive symptoms and high BMI (all P values > 0.05). For the combined effects of the 7 dimensions of personality traits, we found an elevated risk of co-occurrence of depressive symptoms and high BMI per 1-SD increase in the personality trait risk scores (OR (95% CI), single measurement at the last follow-up: 2.01, 1.66 to 2.43; trajectory classification using the repeated measurements 2.30, 1.55 to 3.42; average level using the repeated measurements: 2.27, 1.93 to 2.67). In this national cohort in China, personality traits were found to be associated with the co-occurrence of depressive symptoms and high BMI from adolescence to early adulthood. These findings highlight the importance of stratifying individuals based on their personality traits and providing targeted interventions for those at risk of comorbid depression and obesity.

Personality traits and co-occurrence of depressive symptoms and high BMI: a prospective cohort study.

We assess the associations between personality traits and co-occurrence of depressive symptoms and high BMI from adolescence to early adulthood. We employed a nationally representative cohort in China from 2010 to 2020 year. We included adolescents aged 10-19 years without depressive symptoms and unhealthy weight status (obesity, overweight, or thinness) at baseline and excluded those without any measurement of depressive symptoms or BMI at follow-ups. We assessed baseline personality traits in 7 dimensions of conscientiousness, openness, neuroticism, agreeableness, extraversion, self-esteem, and responsibility. We also assessed the combined effects of these 7 dimensions of personality traits by generating individual-level personality trait risk scores based on the weighted sum of all these 7 dimensions of personality traits. We measured the co-occurrence of depressive symptoms and high BMI using both a single measurement of depressive symptoms and BMI at the last follow-up and repeated measurements of them over 10 years. We used the multinomial logistic regression models to examine the exposure-outcome associations. At baseline, we included 1778 individuals (mean age: 14.4 year; female: 853 (48.0%)). At follow-ups, we observed increased risk of co-occurrence of depressive symptoms and high BMI per 1-SD increase in neuroticism score (1.95-2.38 odds ratio) or 1-SD decrease in self-esteem and conscientiousness (0.63-0.80 odds ratio; all P values < 0.05); we observed no evidence of associations between openness, agreeableness, extraversion, or responsibility and the risk of co-occurrence of depressive symptoms and high BMI (all P values > 0.05). For the combined effects of the 7 dimensions of personality traits, we found an elevated risk of co-occurrence of depressive symptoms and high BMI per 1-SD increase in the personality trait risk scores (OR (95% CI), single measurement at the last follow-up: 2.01, 1.66 to 2.43; trajectory classification using the repeated measurements 2.30, 1.55 to 3.42; average level using the repeated measurements: 2.27, 1.93 to 2.67). In this national cohort in China, personality traits were found to be associated with the co-occurrence of depressive symptoms and high BMI from adolescence to early adulthood. These findings highlight the importance of stratifying individuals based on their personality traits and providing targeted interventions for those at risk of comorbid depression and obesity.

Statistical analysis of self-reported health conditions in cohort studies: handling of missing onset age

ObjectivesThis paper discusses methodological challenges in epidemiological association analysis of a time-to-event outcome and hypothesized risk factors, where age/time at the onset of the outcome may be missing in some cases, a condition commonly encountered when the outcome is self-reported. Study Design and SettingA cohort study with long-term follow-up for outcome ascertainment such as the Childhood Cancer Survivor Study (CCSS), a large cohort study of 5-year survivors of childhood cancer diagnosed in 1970–1999 in which occurrences and age at onset of various chronic health conditions (CHCs) are self-reported in surveys. Simple methods for handling missing onset age and their potential bias in the exposure-outcome association inference are discussed. The interval-censored method is discussed as a remedy for handling this problem. The finite sample performance of these approaches is compared through Monte Carlo simulations. Examples from the CCSS include four CHCs (diabetes, myocardial infarction, osteoporosis/osteopenia, and growth hormone deficiency). ResultsThe interval-censored method is useable in practice using the standard statistical software. The simulation study showed that the regression coefficient estimates from the ‘Interval censored’ method consistently displayed reduced bias and, in most cases, smaller standard deviations, resulting in smaller mean square errors, compared to those from the simple approaches, regardless of the proportion of subjects with an event of interest, the proportion of missing onset age, and the sample size. ConclusionThe interval-censored method is a statistically valid and practical approach to the association analysis of self-reported time-to-event data when onset age may be missing. While the simpler approaches that force such data into complete data may enable the standard analytic methods to be applicable, there is considerable loss in both accuracy and precision relative to the interval-censored method.

Familial confounding or measurement error? How to interpret findings from sibling and co-twin control studies

Epidemiological researchers often examine associations between risk factors and health outcomes in non-experimental designs. Observed associations may be causal or confounded by unmeasured factors. Sibling and co-twin control studies account for familial confounding by comparing exposure levels among siblings (or twins). If the exposure-outcome association is causal, the siblings should also differ regarding the outcome. However, such studies may sometimes introduce more bias than they alleviate. Measurement error in the exposure may bias results and lead to erroneous conclusions that truly causal exposure-outcome associations are confounded by familial factors. The current study used Monte Carlo simulations to examine bias due to measurement error in sibling control models when the observed exposure-outcome association is truly causal. The results showed that decreasing exposure reliability and increasing sibling-correlations in the exposure led to deflated exposure-outcome associations and inflated associations between the family mean of the exposure and the outcome. The risk of falsely concluding that causal associations were confounded was high in many situations. For example, when exposure reliability was 0.7 and the observed sibling-correlation was r = 0.4, about 30–90% of the samples (n = 2,000) provided results supporting a false conclusion of confounding, depending on how p-values were interpreted as evidence for a family effect on the outcome. The current results have practical importance for epidemiological researchers conducting or reviewing sibling and co-twin control studies and may improve our understanding of observed associations between risk factors and health outcomes. We have developed an app (SibSim) providing simulations of many situations not presented in this paper.

The OCCHLTH Mnemonic-Construction and Content of a Tool for Increasing Awareness of Occupational Illness and Injury.

Unidentified or nonmitigated occupational illnesses and injuries can complicate disease management. The "occupational health" (OCCHLTH) mnemonic aims to raise awareness of work-related exposures and associated illnesses and injuries. Occupational safety and health history-taking elements were combined with peer-reviewed information [from the PubMed database (first review January 1, 2000, to February 8, 2016; updated to February 8, 2021)] about workplace exposure-outcome associations to create the mnemonic. Seven components constitute the OCCHLTH mnemonic. Literature results support its categories and subcategories. Three components represent symptom onset and health conditions. Four represent occupational exposures. Evaluating published occupational illness cases explored mnemonic applicability. Awareness of occupational risk factors can affect clinical decision-making. The OCCHLTH mnemonic encourages consideration of occupational causes of illness and injury to optimize patient care. Further evaluation of the utility of the OCCHLTH mnemonic is needed.

Post-diagnosis dietary factors, supplement use and colorectal cancer prognosis: A Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis.

The role of diet in colorectal cancer prognosis is not well understood and specific lifestyle recommendations are lacking. We searched for randomised controlled trials (RCTs) and longitudinal observational studies on post-diagnosis dietary factors, supplement use and colorectal cancer survival outcomes in PubMed and Embase from inception until 28th February 2022. Random-effects dose-response meta-analyses were conducted when at least three studies had sufficient information. The evidence was interpreted and graded by the CUP Global independent Expert Committee on Cancer Survivorship and Expert Panel. Five RCTs and 35 observational studies were included (30,242 cases, over 8700 all-cause and 2100 colorectal cancer deaths, 3700 progression, recurrence, or disease-free events). Meta-analyses, including 3-10 observational studies each, were conducted for: whole grains, nuts/peanuts, red and processed meat, dairy products, sugary drinks, artificially sweetened beverages, coffee, alcohol, dietary glycaemic load/index, insulin load/index, marine omega-3 polyunsaturated fatty acids, supplemental calcium, circulating 25-hydroxyvitamin D (25[OH]D) and all-cause mortality; for alcohol, supplemental calcium, circulating 25(OH)D and colorectal cancer-specific mortality; and for circulating 25(OH)D and recurrence/disease-free survival. The overall evidence was graded as 'limited'. The inverse associations between healthy dietary and/or lifestyle patterns (including diets that comprised plant-based foods), whole grains, total, caffeinated, or decaffeinated coffee and all-cause mortality and the positive associations between unhealthy dietary patterns, sugary drinks and all-cause mortality provided 'limited-suggestive' evidence. All other exposure-outcome associations provided 'limited-no conclusion' evidence. Additional, well-conducted cohort studies and carefully designed RCTs are needed to develop specific lifestyle recommendations for colorectal cancer survivors.

Childhood maltreatment, parenting style and anxiety in Chinese youths: A case-control study

BackgroundAlthough evidence in supporting the associations between childhood maltreatment (CM), parenting style and anxiety in children and adolescents exists, few high-quality analytical epidemiological studies which focusing on clinically diagnosed anxiety disorders (AD) had been published. ObjectiveThe aim of this study was to further corroborate the associations between CM, parenting style, and AD in a large representative sample of Chinese children and adolescents. Participants and settingStudy subjects were derived from the Mental Health Survey for Children and Adolescents in Yunnan (MHSCAY), a population-based cross-sectional program. MethodsIndividually matched case-control study design was adopted. Univariate and multivariate conditional binary logistic regression models were used to estimate the associations between CM, parenting style and AD. Dose-response trends were estimated using the Cochran-Armitage Chi-square test. A series of stratified analyses were conducted to explore effect modification on exposure-outcome association by some important features. ResultsTotally we screened out 202 cases and 404 matched controls, with an age mean of 14.43 years. Conditional logistic regression models revealed that EA and a higher level of parental over-protection were significantly associated with increased risk of AD, with adjusted ORs of 3.39 (95 % CI: 2.07–5.56) and 1.93 (95 % CI: 1.28–2.90). Stratified analysis identified noticeable effect modification by sex, age, and whether the only child in the family. ConclusionsMajor findings of this study suggested that children and adolescents who had experienced EA or raised up by over-protective parents are at increased risk of AD. Targeted intervention measures should be developed and implemented for these high-risk youths.

Contributions of Synthetic Chemicals to Autoimmune Disease Development and Occurrence.

Exposure to many synthetic chemicals has been linked to a variety of adverse human health effects, including autoimmune diseases. In this scoping review, we summarize recent evidence detailing the effects of synthetic environmental chemicals on autoimmune diseases and highlight current research gaps and recommendations for future studies. We identified 68 recent publications related to environmental chemical exposures and autoimmune diseases. Most studies evaluated exposure to persistent environmental chemicals and autoimmune conditions including rheumatoid arthritis (RA), systemic lupus (SLE), systemic sclerosis (SSc), and ulcerative colitis (UC) and Crohn's disease. Results of recent original research studies were mixed, and available data for some exposure-outcome associations were particularly limited. PFAS and autoimmune inflammatory bowel diseases (UC and CD) and pesticides and RA appeared to be the most frequently studied exposure-outcome associations among recent publications, despite a historical research focus on solvents. Recent studies have provided additional evidence for the associations of exposure to synthetic chemicals with certain autoimmune conditions. However, impacts on other autoimmune outcomes, particularly less prevalent conditions, remain unclear. Owing to the ubiquitous nature of many of these exposures and their potential impacts on autoimmune risk, additional studies are needed to better evaluate these relationships, particularly for understudied autoimmune conditions. Future research should include larger longitudinal studies and studies among more diverse populations to elucidate the temporal relationships between exposure-outcome pairs and to identify potential population subgroups that may be more adversely impacted by immune modulation caused by exposure to these chemicals.

Association between intrapartum fetal pulse oximetry and adverse perinatal and long-term outcomes: a systematic review and meta-analysis protocol.

Current methods of intrapartum fetal monitoring based on heart rate, increase the rates of operative delivery but do not prevent or accurately detect fetal hypoxic brain injury. There is a need for more accurate methods of intrapartum fetal surveillance that will decrease the incidence of adverse perinatal and long-term neurodevelopmental outcomes while maintaining the lowest possible rate of obstetric intervention. Fetal pulse oximetry (FPO) is a technology that may contribute to improved intrapartum fetal wellbeing evaluation by providing a non-invasive measurement of fetal oxygenation status. This systematic review and meta-analysis aims to synthesise the evidence examining the association between intrapartum fetal oxygen saturation levels and adverse perinatal and long-term outcomes in the offspring. We will include randomised control trials (RCTs), cohort, cross-sectional and case-control studies which examine the use of FPO during labour as a means of measuring intrapartum fetal oxygen saturation and assess its effectiveness at detecting adverse perinatal and long-term outcomes compared to existing intrapartum surveillance methods. A detailed systematic search of PubMed, EMBASE, CINAHL, The Cochrane Library, Web of Science, ClinicalTrials.Gov and WHO ICTRP will be conducted following a detailed search strategy until February 2024. Three authors will independently review titles, abstracts and full text of articles. Two reviewers will independently extract data using a pre-defined data extraction form and assess the quality of included studies using the Risk of Bias tool for RCTs and Newcastle-Ottawa Scale for observational studies. The grading of recommendations, assessment, development, and evaluation (GRADE) approach will be used to evaluate the certainty of the evidence. We will use random-effects meta-analysis for each exposure-outcome association to calculate pooled estimates using the generic variance method. This systematic review will follow the Preferred Reporting Items for Systematic reviews and Meta-analyses and MOOSE guidelines. CRD42023457368 (04/09/2023).

Abstract P503: Syphilis Infection and Increased Odds of Cardiovascular Morbidity

Background: Cardiovascular disease (CVD) is the number one cause of death in the United States and around the world. Syphilis is a sexually transmitted infection conferred by the spirochete Treponema pallidum which demonstrates a unique affinity for the human CV system. It is understood that Treponemal invasion of vascular and cardiac tissue, in the absence of treatment, may result in the CV manifestations of late, tertiary syphilis including: aortic aneurysm, aortic insufficiency, coronary artery disease (CAD), and stroke. Recent literature has suggested that chronic kidney disease (CKD) may also be among these sequalae. It is the current understanding that syphilitic CVD morbidity is effectively prevented and treated with the standard of care (SOC) antimicrobial therapy dictated for early and late syphilis, however, there is a relative paucity of data to support this. In light of the ongoing syphilis epidemic in the United States, our group sought to revisit and evaluate these central tenets of syphilis care. Methods: A preliminary, 10-year retrospective analysis (01/2013-12/31/2022) of deidentified electronic medical records (EMR) from a California-based academic health system was undertaken. The study population consisted of all health system patients &gt;18 who were seen during the study period. The exposure of interest consisted of ICD-10 codes representative of syphilis infection with CVD outcomes defined as ICD-10 diagnoses reflective of the known, principle clinical manifestations of tertiary syphilis as well as CKD and HTN. Unadjusted, bivariate analysis was performed for preliminary assessment of exposure-outcome association. Results: 3,559,370 unique EMR were included in final analysis. 5,915 patients were found to have a diagnosis of syphilis. The majority of patients diagnosed with syphilis had documentation of treatment. Patients with history of syphilis infection had significantly higher odds of aortic aneurysm (OR = 6.17; 95%CI = 5.07-7.5), CAD (OR = 5.81; 95%CI = 5.37-6.27), aortic insufficiency (OR = 5.52; 95%CI = 4.47-6.81), stroke (OR = 5; 95%CI = 4.58-5.46), HTN (OR = 8.38; 95%CI = 7.94-8.85), and CKD (OR = 10.94; 95%CI = 10.28-11.64) relative to uninfected patients. Conclusion: Preliminary analysis indicates syphilis infection to be associated with significantly increased odds of CVD morbidity across all outcomes measured including CKD. These data suggest that the CV impact of syphilis may be broader than previously understood and raise concern for a clinically significant limitation to the current SOC in protection against CVD morbidity. A follow-up study is underway which will utilize multivariate logistic regression analysis to determine the independent effect of syphilis infection adjusting for multiple confounders to further clarify our preliminary results.

The unique risk factor profile of triple-negative breast cancer: a comprehensive meta-analysis.

Triple-negative breast cancer (TNBC) has a poor prognosis compared with other breast cancer subtypes. This systematic review and meta-analysis examines whether known risk factors for breast cancer are also associated with TNBC in adult women. EMBASE, Medline, SCOPUS, and gray literature were queried with no limit on the date or language of publication. The exposures of interest included parity, breastfeeding, duration of breastfeeding, age at menarche, age at first live birth, oral contraceptive (OC) use, duration of OC use, use of menopausal hormone therapy (MHT), family history, body mass index (BMI), alcohol use, smoking, and breast density. The main outcome of interest was TNBC. Study quality was determined using the Newcastle-Ottawa scale for case control studies and cohort studies. We estimated weighted odds ratios from random effects models to study the exposure-outcome associations. Protocol was registered under the number: PROSPERO 2021 CRD42021254594. Thirty-three studies were included. Family history, longer duration of OC use, and higher breast density were significantly associated with increased risk for TNBC, whereas later age at menarche, later age at first birth, and breastfeeding were protective against TNBC. Parity, MHT, alcohol, smoking, and BMI were not significantly associated with TNBC overall, but higher parity was associated with higher risk among Black women. Our findings highlight that TNBC has a distinct risk factor profile compared with overall breast cancer. This can be the foundational work in identification of actionable TNBC risk factors to improve prevention and early detection of these poor prognosis breast tumors.

Effect of viral hepatitis on type 2 diabetes: A Mendelian randomization study.

The effects of viral hepatitis (VH) on type 2 diabetes (T2D) remain controversial. To analyze the causal correlation between different types of VH and T2D using Mendelian randomization (MR). Single nucleotide polymorphisms of VH, chronic hepatitis B (CHB), chronic hepatitis C (CHC) and T2D were obtained from the BioBank Japan Project, European Bioinformatics Institute, and FinnGen. Inverse variance weighted, MR-Egger, and weighted median were used to test exposure-outcome associations. The MR-Egger intercept analysis and Cochran's Q test were used to assess horizontal pleiotropy and heterogeneity, respectively. Leave-one-out sensitivity analysis was used to evaluate the robustness of the MR analysis results. The MR analysis showed no significant causal relationship between VH and T2D in Europeans [odds ratio (OR) = 1.028; 95% confidence interval (CI): 0.995-1.062, P = 0.101]. There was a negative causal association between CHB and T2D among East Asians (OR = 0.949; 95%CI: 0.931-0.968, P < 0.001), while there was no significant causal association between CHC and T2D among East Asians (OR = 1.018; 95%CI: 0.959-1.081, P = 0.551). Intercept analysis and Cochran's Q test showed no horizontal pleiotropy or heterogeneity (P > 0.05). Sensitivity analysis showed that the results were robust. Among East Asians, CHB is associated with a reduced T2D risk, but this association is limited by HBV load and cirrhosis. Although VH among Europeans and CHC among East Asians are not associated with the risk of T2D, focusing on blood glucose in patients with CHC is still relevant for the early detection of T2D induced by CHC-mediated pathways of hepatic steatosis, liver fibrosis, and cirrhosis.

Toxic metals and essential trace elements in placenta and their relation to placental function

IntroductionPlacental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. ObjectiveTo assess the impact of toxic and essential trace elements in placenta on placental function. MethodsToxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. ResultsMedian cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 μg/kg, respectively. In the adjusted regression, selenium (>147 μg/kg) was inversely associated with placental weight (B: −158; 95 % CI: −246, −71, per doubling), as was lead at low selenium (B: −23.6; 95 % CI: −43.2, −4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: −0.01; 95 % CI: −0.019, −0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: −11; 95 % CI: −20, −0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. ConclusionAmong the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation.

Cross-institution natural language processing for reliable clinical association studies: a methodological exploration

ObjectivesNatural language processing (NLP) of clinical notes in electronic medical records is increasingly used to extract otherwise sparsely available patient characteristics, to assess their association with relevant health outcomes. Manual data curation is resource intensive and NLP methods make these studies more feasible. However, the methodology of using NLP methods reliably in clinical research is understudied. The objective of this study is to investigate how NLP models could be used to extract study variables (specifically exposures) to reliably conduct exposure-outcome association studies. Study Design and SettingIn a convenience sample of patients admitted to the intensive care unit of a US academic health system, multiple association studies are conducted, comparing the association estimates based on NLP-extracted vs. manually extracted exposure variables. The association studies varied in NLP model architecture (Bidirectional Encoder Decoder from Transformers, Long Short-Term Memory), training paradigm (training a new model, fine-tuning an existing external model), extracted exposures (employment status, living status, and substance use), health outcomes (having a do-not-resuscitate/intubate code, length of stay, and in-hospital mortality), missing data handling (multiple imputation vs. complete case analysis), and the application of measurement error correction (via regression calibration). ResultsThe study was conducted on 1,174 participants (median [interquartile range] age, 61 [50, 73] years; 60.6% male). Additionally, up to 500 discharge reports of participants from the same health system and 2,528 reports of participants from an external health system were used to train the NLP models. Substantial differences were found between the associations based on NLP-extracted and manually extracted exposures under all settings. The error in association was only weakly correlated with the overall F1 score of the NLP models. ConclusionAssociations estimated using NLP-extracted exposures should be interpreted with caution. Further research is needed to set conditions for reliable use of NLP in medical association studies.

The U.S. PFAS exposure burden calculator for 2017–2018: Application to the HOME Study, with comparison of epidemiological findings from NHANES

BackgroundThe 2017–2018 U.S. PFAS exposure burden calculator was designed to provide a summary exposure score for per- and polyfluoroalkyl substances (PFAS) mixtures using targeted PFAS analyte data. Its aim was to place PFAS burden score estimates onto a common scale based on nationally representative U.S. reference ranges from 2017 to 2018, enabling comparisons of overall PFAS burden scores across studies even if they did not measure the same set of PFAS analytes. ObjectiveTo use the U.S. PFAS exposure burden calculator for comparing the same mixture of PFAS compounds in similarly aged adolescents and their associations with cardiometabolic outcomes in the HOME Study and NHANES between 2015 and 2018. MethodsWe applied the PFAS burden calculator to 8 PFAS analytes measured in the serum of adolescents from the HOME Study (Cincinnati, Ohio; age range 11–14 years; years: 2016–2019; n = 207) and NHANES (US; age range 12–14 years; years 2015–2018; n = 245). We used the non-parametric Mann-Whitney U test and chi-squared test to compare the two study samples. In both studies, we examined associations of PFAS burden scores with the same cardiometabolic outcomes, adjusted for the same core set of covariates using regression analyses. We conducted sensitivity analyses to verify robustness of exposure-outcome associations, by accounting for measurement error of PFAS burden scores. ResultsPFAS burden scores were significantly different (p = 0.004) between the HOME Study (median: 0.00, interquartile range − 0.37, 0.34) and the NHANES samples (median: 0.04, IQR -0.11, 0.54), while no significant difference was found for PFAS summed concentrations (p = 0.661). In the HOME Study, an interquartile (IQR) increase in PFAS burden score was associated with higher total cholesterol [7.0 mg/dL, 95% CI: 0.6, 13.4]; HDL [2.8 mg/dL, 95% CI: 0.4, 5.2]; LDL [5.9 mg/dL, 95% CI: 0.5, 11.3], insulin [0.1 log(mIU/L), 95% CI: 0.01, 0.2], and HOMA-IR [0.1, 95% CI: 0.01, 0.2]. In NHANES, an IQR increase in PFAS burden score was associated with higher diastolic blood pressure [2.4 mmHg, 95% CI: 0.4, 4.4] but not with other outcomes. Sensitivity analyses in the HOME Study and NHANES were consistent with the main findings. ConclusionsPerformance of the U.S. PFAS exposure burden calculator was similar in a local versus national sample of adolescents, and may be a useful tool for the assessment of PFAS mixtures across studies.

Disparities in Cytomegalovirus Infection Rates by Race and Ethnicity among Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients at a Single Center

Previous literature has reported cytomegalovirus (CMV) infection rate disparities among racial/ethnic groups of hematopoietic cell transplantation (HCT) recipients. Because race and ethnicity categorizations are social constructs unlikely to affect biological systems, it is likely there are covariates on the pathway to CMV detection, known as mediators, that can explain the observed disparity. Recent developments in mediation analysis methods enable the analysis of time-to-event outcomes, allowing an investigation of these disparities to also consider the timing of CMV infection detection relative to HCT. This study aimed to explore whether racial and ethnic CMV infection disparities existed within a population of HCT recipients at our center, and whether clinical covariates explained any observed association. The study cohort included all recipients of allogeneic HCT performed at the Children's Hospital of Philadelphia between January 2004 and April 2017 who were CMV PCR-negative pretransplantation, had known donor/recipient CMV serology, and were under blood CMV PCR surveillance. Subjects were followed for 100 days post-HCT. Accelerated failure time models using subject's reported race/ethnicity, dichotomized into non-Hispanic White (NHW) and non-NHW, and exposure and time to CMV detection as outcomes examined whether selected clinical factors-donor/recipient CMV serostatus, recipient age, indication for HCT, hematopoietic cell source, match quality-mediated any identified exposure-outcome association. The analysis included 348 HCTs performed in 335 subjects, with 86 episodes (24.7%) in which CMV was detected via PCR analysis. The accelerated failure time model without mediators estimated that non-NHW subjects had fewer CMV-free survival days (time ratio, .21; 95% confidence interval, .10 to .44). Any hypothesized mediator mediated at most 5% of the total association between race/ethnicity and time to CMV detection. Non-NHW HCT recipients had fewer CMV-free survival days than NHW recipients; none of the clinical factors hypothesized to mediate this association accounted for a significant component of total association. Further research should focus on nonclinical factors influenced by systemic racism to better understand their effect on CMV infection among HCT recipients.

Associations between prenatal exposure to per- and polyfluoroalkyl substances and wheezing and asthma symptoms in 4-year-old children: The Japan Environment and Children's Study

The effects of early-life exposure to per- and polyfluoroalkyl substances (PFAS) on the onset of asthma in children have been unclear. We examined the association between prenatal PFAS exposure and wheezing and asthma symptoms among 4-year-old children in a total of 17,856 mother-child pairs from the Japan Environment and Children's Study. Maternal first-trimester serum concentrations of six PFAS were used for the exposure assessment. We defined “wheeze ever,” “current wheeze,” “current symptoms of severe asthma,” and “asthma ever” at the age of 4 years by the responses to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, and “doctor-diagnosed asthma” by the response to a corresponding question. Multivariate logistic regression models were used to examine exposure-outcome associations. Our findings revealed that doubling of the PFOA concentration was associated with a reduced occurrence of “wheeze ever,” yielding an adjusted odds ratio of 0.94 (95% CI: 0.90–0.98). Also, doubling in the concentrations of PFOA and PFHxS was associated with a decreased prevalence of “asthma ever,” with adjusted odds ratios of 0.94 (95% CI: 0.88–1.00) and 0.95 (95% CI: 0.90–0.99), respectively. However, these associations were not significant after applying the Bonferroni correction. The estimated exposure-response curves were nearly linear with a subtle or flat slope. When stratified by the child's sex or the mother's history of asthma, most of the estimated confidence intervals were overlapped between each pair of strata. Regional stratification analysis indicated low-to-moderate heterogeneity in 12 exposure-outcome pairs and moderate-to-high heterogeneity in 9 out of the 30 examined pairs. This study found no clear associations between prenatal PFAS exposure and the prevalence of wheezing and asthma among children at the age of 4 years.