Biases in Electronic Health Records Data for Generating Real-World Evidence: An Overview.

Electronic Health Records (EHR) are increasingly being perceived as a unique source of data for clinical research as they provide unprecedentedly large volumes of real-time data from real-world settings. In this review of the secondary uses of EHR, we identify the anticipated breadth of opportunities, pointing out the data deficiencies and potential biases that are likely to limit the search for true causal relationships. This paper provides a comprehensive overview of the types of biases that arise along the pathways that generate real-world evidence and the sources of these biases. We distinguish between two levels in the production of EHR data where biases are likely to arise: (i) at the healthcare system level, where the principal source of bias resides in access to, and provision of, medical care, and in the acquisition and documentation of medical and administrative data; and (ii) at the research level, where biases arise from the processes of extracting, analyzing, and interpreting these data. Due to the plethora of biases, mainly in the form of selection and information bias, we conclude with advising extreme caution about making causal inferences based on secondary uses of EHRs.

Association of the Infant Gut Microbiome with Temperament at Nine Months of Age: A Michigan Cohort Study.

Though studies in animals and humans link the gut microbiota to brain development and control of behavior, little research has examined this connection in healthy infants. This prospective study could determine associations between infant gut microbiota at 3 months, and infant temperament at 9 months, in a prospective pregnancy cohort (Michigan Archive for Research on Child Health; n = 159). Microbiota profiling with 16S rRNA gene sequencing was conducted on fecal samples obtained at 3 months of age. Based on the relative abundance of gut microbiotas, three groups were identified, and each group was characterized by different microbes. Infant temperament outcomes were reported by mothers using the Infant Behavior Questionnaire-Revised Very Short Form at a mean age of 9.4 months. Fully adjusted multivariate linear regression models showed that certain clusters were associated with higher negative emotionality scores, prominently among infants who had poor vitamin D intake. However, no associations were evident between gut microbiota clusters and temperament scales after FDR correction. After using three differential abundance tools, Firmicutes was associated with higher positive affect/surgency scores, whereas Clostridioides was associated with lower scores. An association between the gut microbiota and early infancy temperament was observed; thus, this study warrants replication, with a particular focus on vitamin D moderation.

Aspects of Physical Activity and Quality of Life in Adults with Cerebral Palsy.

Background: Physical activity and sedentary behavior may differentially impact health-related quality of life in adults with cerebral palsy. Objective: The present investigation assessed the independent relationships between aspects of physical activity and sedentary behavior related to health related quality of life in adults with cerebral palsy. Methods: Through a cross-sectional online survey of 118 adults with cerebral palsy, participants self-reported the extent of their functional impairments using the Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System; while mental and physical health-related quality of life were assessed using the RAND-36. Physical activity and sedentary behavior were quantified using the Physical Activity and Disability Survey-Revised and Sedentary Behavior Questionnaire, respectively. Results: Accounting for potential confounding influences of impairments, neither exercise-related physical activity, leisure time- related physical activity, occupational physical activity, nor sedentary behavior was associated with any characterization of health-related quality of life. However, greater engagement in general lifestyle physical activity was related to superior mental health-related quality of life. Conclusion: These findings provide initial evidence to suggest that focusing public health and therapeutic recommendations for individuals with cerebral palsy on general physical activity engagement throughout the day might incur potential benefits for enhancing mental health- related quality of life in this population.

Maternal Pre-Pregnancy BMI, Breastfeeding, and Child BMI.

OBJECTIVES: Breastfeeding practices may protect against offspring obesity, but this relationship is understudied among women with obesity. We describe the associations between breastfeeding practices and child BMI for age z-score (BMIz), stratified by maternal BMI. METHODS: We analyzed 8134 dyads from 21 cohorts in the Environmental Influences on Child Health Outcomes Program. Dyads with data for maternal pre-pregnancy BMI, infant feeding practices, and ≥1 child BMI assessment between the ages of 2 and 6 years were included. The associations between breastfeeding practices and continuous child BMIz were assessed by using multivariable linear mixed models. RESULTS: Maternal pre-pregnancy BMI category prevalence was underweight: 2.5%, healthy weight: 45.8%, overweight: 26.0%, and obese: 25.6%. Median child ages at the cessation of any breastfeeding and exclusive breastfeeding across the 4 BMI categories were 19, 26, 24, and 17 weeks and 12, 20, 17, and 12 weeks, respectively. Results were in the hypothesized directions for BMI categories. Three months of any breastfeeding was associated with a lower BMIz among children whose mothers were a healthy weight (-0.02 [-0.04 to 0.001], P = .06), overweight (-0.04 [-0.07 to -0.004], P = .03), or obese (-0.04 [-0.07 to -0.006], P = .02). Three months of exclusive breastfeeding was associated with a lower BMIz among children whose mothers were a healthy weight (-0.06 [-0.10 to -0.02], P = .002), overweight (-0.05 [-0.10 to 0.005], P = .07), or obese (-0.08 [-0.12 to -0.03], P = .001). CONCLUSIONS: Human milk exposure, regardless of maternal BMI category, was associated with a lower child BMIz in the Environmental Influences on Child Health Outcomes cohorts, supporting breastfeeding recommendations as a potential strategy for decreasing the risk of offspring obesity.

Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis.

This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison. Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI = 0.24-0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma (CCP) (OR = 0.69 [95% CI = 0.53-0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48-1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72-0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions. Omicron sublineages (XBB and BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.

Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

The contribution of epidemiology to the understanding of neurodevelopmental disabilities.

Epidemiological approaches have played an important role in creating better understanding of developmental disabilities by delineating their frequency in populations and changes in their frequency over time, by identifying etiological factors, and by documenting pathways to prevention. Both cerebral palsy (CP) and mild intellectual disability are declining in frequency in high-income countries. The diagnosis of autism spectrum disorder has increased in recent decades, but much of this increase is a result of changing approaches to ascertainment and recording. Epidemiological studies have found that most CP is not of birth-asphyxial origin, that most febrile seizures do not pose a major risk for epilepsy, and that folic acid deficiency may contribute to developmental disabilities apart from its effect on neural tube defects. Epidemiological research has shown that an important fraction of neural tube defects and virtually all cases of Reye syndrome are preventable, and recent trials have shown ways to prevent CP. Early psychoeducational interventions in children at risk for mild intellectual disability are an effective and valuable societal investment. Very large population-based studies starting in pregnancy have been launched in Norway, Denmark, and Japan in recent years and these and other population studies promise to continue the epidemiological contribution to a better understanding of developmental disabilities.

Convalescent plasma therapy in COVID-19: Unravelling the data using the principles of antibody therapy.

INTRODUCTION: When the COVID-19 pandemic struck no specific therapies were available and many turned to COVID-19 convalescent plasma (CCP), a form of antibody therapy. The literature provides mixed evidence for CCP efficacy. AREAS COVERED: PubMed was searched using the words COVID-19 and convalescent plasma and individual study designs were evaluated for adherence to the three principles of antibody therapy, i.e. that plasma 1) contain specific antibody; 2) have enough specific antibody to mediate a biological effect; and 3) be administered early in the course of disease. Using this approach, a diverse and seemingly contradictory collection of clinical findings was distilled into a consistent picture whereby CCP was effective when used according to the above principles of antibody therapy. In addition, CCP therapy in immunocompromised patients is useful at any time in the course of disease. EXPERT OPINION: CCP is safe and effective when used appropriately. Today, most of humanity has some immunity to SARS-CoV-2 from vaccines and infection, which has lessened the need for CCP in the general population. However, COVID-19 in immunocompromised patients is a major therapeutic challenge, and with the deauthorization of all SARS-CoV-2-spike protein-directed monoclonal antibodies, CCP is the only antibody therapy available for this population.

Health Care Utilization During the COVID-19 Pandemic Among Individuals Born Preterm.

Importance: Limited data exist on pediatric health care utilization during the COVID-19 pandemic among children and young adults born preterm. Objective: To investigate differences in health care use related to COVID-19 concerns during the pandemic among children and young adults born preterm vs those born at term. Design, Setting, and Participants: In this cohort study, questionnaires regarding COVID-19 and health care utilization were completed by 1691 mother-offspring pairs from 42 pediatric cohorts in the National Institutes of Health Environmental Influences on Child Health Outcomes Program. Children and young adults (ages 1-18 years) in these analyses were born between 2003 and 2021. Data were recorded by the August 31, 2021, data-lock date and were analyzed between October 2021 and October 2022. Exposures: Premature birth (<37 weeks' gestation). Main Outcomes and Measures: The main outcome was health care utilization related to COVID-19 concerns (hospitalization, in-person clinic or emergency department visit, phone or telehealth evaluations). Individuals born preterm vs term (≥37 weeks' gestation) and differences among preterm subgroups of individuals (<28 weeks', 28-36 weeks' vs ≥37 weeks' gestation) were assessed. Generalized estimating equations assessed population odds for health care used and related symptoms, controlling for maternal age, education, and psychiatric disorder; offspring history of bronchopulmonary dysplasia (BPD) or asthma; and timing and age at COVID-19 questionnaire completion. Results: Data from 1691 children and young adults were analyzed; among 270 individuals born preterm, the mean (SD) age at survey completion was 8.8 (4.4) years, 151 (55.9%) were male, and 193 (71.5%) had a history of BPD or asthma diagnosis. Among 1421 comparison individuals with term birth, the mean (SD) age at survey completion was 8.4 (2.4) years, 749 (52.7%) were male, and 233 (16.4%) had a history of BPD or asthma. Preterm subgroups included 159 individuals (58.5%) born at less than 28 weeks' gestation. In adjusted analyses, individuals born preterm had a significantly higher odds of health care utilization related to COVID-19 concerns (adjusted odds ratio [aOR], 1.70; 95% CI, 1.21-2.38) compared with term-born individuals; similar differences were also seen for the subgroup of individuals born at less than 28 weeks' gestation (aOR, 2.15; 95% CI, 1.40-3.29). Maternal history of a psychiatric disorder was a significant covariate associated with health care utilization for all individuals (aOR, 1.44; 95% CI, 1.17-1.78). Conclusions and Relevance: These findings suggest that during the COVID-19 pandemic, children and young adults born preterm were more likely to have used health care related to COVID-19 concerns compared with their term-born peers, independent of a history of BPD or asthma. Further exploration of factors associated with COVID-19-related health care use may facilitate refinement of care models.

The Associations of Maternal Health Characteristics, Newborn Metabolite Concentrations, and Child Body Mass Index among US Children in the ECHO Program.

We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aß 0.05 [95% CI 0.03, 0.07]; replication: aß 0.04 [95% CI 0.006, 0.06]; C2: discovery: aß 0.04 [95% CI 0.003, 0.08]; replication: aß 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1-3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns.

Comparison of methanol fixation versus cryopreservation of the placenta for metabolomics analysis.

Methods for collection of placental tissue at room temperature for metabolic profiling are described. Specimens were excised from the maternal side of the placenta and immediately flash frozen or fixed and stored for 1, 6, 12, 24, or 48 h in 80% methanol. Untargeted metabolic profiling was performed on both the methanol-fixed tissue and the methanol extract. Data were analyzed using Gaussian generalized estimating equations, two sample t-tests with false discovery rate (FDR) corrections, and principal components analysis. Methanol-fixed tissue samples and methanol extracts had a similar number of metabolites (p = 0.45, p = 0.21 in positive vs. negative ion mode). In positive ion mode, when compared to flash frozen tissue, both the methanol extract and methanol-fixed tissue (6 h) had a higher number of metabolites detected (146 additional metabolites, pFDR = 0.020; 149 additional metabolites, pFDR = 0.017; respectively), but these associations were not found in negative ion mode (all pFDR ≥ 0.05). Principle components analysis demonstrated separation of the metabolite features in the methanol extract, but similarity between methanol-fixed tissue and flash frozen tissue. These results show that placental tissue samples collected in 80% methanol at room temperature can yield similar metabolic data to flash frozen specimens.

Outpatient regimens to reduce COVID-19 hospitalisations: a systematic review and meta-analysis of randomized controlled trials.

Background: During pandemics, early outpatient treatments reduce the health system burden. Randomized controlled trials (RCTs) in COVID-19 outpatients have tested therapeutic agents, but no RCT or systematic review has been conducted comparing the efficacy of the main outpatient treatment classes to each other. We aimed in this systematic review of outpatient RCTs in COVID-19 to compare hospitalisation rate reductions with four classes of treatment: convalescent plasma, monoclonal antibodies, small molecule antivirals and repurposed drugs. Methods: We conducted a systematic review and meta-analysis of all COVID-19 outpatient RCTs that included the endpoint of progression to hospitalisation. We assembled, from multiple published and preprint databases, participant characteristics, hospitalisations, resolution of symptoms and mortality from January 2020 to May 21, 2023. The risk of bias from COVID-NMA was incorporated into the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. We measured heterogeneity with I 2 . Meta-analysis by a random or fixed effect model dependent on significant heterogeneity (I 2 >50%) was performed. The protocol was registered in PROSPERO, CRD42022369181. Findings: The search identified 281 studies of which 54 RCTs for 30 diverse interventions were included in the final analysis. These trials, performed largely in unvaccinated cohorts during pre-Omicron waves, focused on populations with at least one COVID-19 hospitalisation risk factor. Grouping by class, monoclonal antibodies (OR=0.31 [95% CI=0.24-0.40]) had highest efficacy, followed by COVID-19 convalescent plasma (CCP) (OR=0.69 [95% CI=0.53 to 0.90]) and small molecule antivirals (OR=0.78 [95% CI=0.48-1.33]) for hospital reduction. Repurposed drugs (OR=0.82 [95% CI-0.72-0.93]) had lower efficacy. Interpretation: Inasmuch as omicron sublineages (XBB and BQ.1.1) are now resistant to monoclonal antibodies, oral antivirals are the preferred treatment in outpatients where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised. Funding: US Department of Defense and National Institute of Health. Research in context: Evidence before this study: We systematically searched the published and preprint data bases for outpatient randomized clinical trials of treatment of COVID-19 disease with hospitalisation as an endpoint. Previous systematic reviews and meta-analyses have confined the reviews to specific classes such as convalescent plasma, monoclonal antibodies, small molecule antivirals or repurposed drugs. Few comparisons have been made between these therapeutic classes. The trials took place both in the pre-vaccination and the vaccination era, spanning periods with dominance of different COVID variants. We sought to compare efficacy between the four classes of treatments listed above when used in outpatient COVID-19 patients as shown in randomized, placebo-controlled trials. Added value of this study: This systematic review and meta-analysis brings together trials that assessed hospitalisation rates in diverse COVID-19 outpatient populations varying in age and comorbidities, permitting us to assess the efficacy of interventions both within and across therapeutic classes. While heterogeneity exists within and between these intervention classes, the meta-analysis can be placed in context of trial diverse populations over variant time periods of the pandemic. At present most of the world population has either had COVID-19 or been vaccinated with a high seropositivity rate, indicating that future placebo-controlled trials will be limited because of the sample sizes required to document hospitalisation outcomes. Implications of all the available evidence: Numerous diverse therapeutic tools need to be ready for a resilient response to changing SARS-CoV-2 variants in both immunocompetent and immunocompromised COVID-19 outpatient populations. To date few head-to-head randomized controlled trials (RCTs) has compared treatment options for COVID-19 outpatients, making comparisons and treatment choices difficult. This systematic review compares outcomes among RCTs of outpatient therapy for COVID-19, taking into account time between onset of symptoms and treatment administration. We found that small-chemical antivirals, convalescent plasma and monoclonal antibodies had comparable efficacy between classes and amongst interventions within the four classes. Monoclonals have lost efficacy with viral mutation, and chemical antivirals have contraindications and adverse events, while intravenous interventions like convalescent plasma or remdesivir remain resilient options for the immunocompromised, and, in the case of CCP, in resource constrained settings with limited availability of oral drugs.

Prenatal Antidepressant Exposures and Autism Spectrum Disorder or Traits: A Retrospective, Multi-Cohort Study.

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

Commentary on "Outcomes of Convalescent Plasma with Defined High versus Lower Neutralizing Antibody Titers against SARS-CoV-2 among Hospitalized Patients: CoronaVirus Inactivating Plasma (CoVIP) Study".

The totality of evidence favors the efficacy of convalescent plasma to treat COVID-19 when high-titer plasma is administered early in the course of disease or to immunocompromised patients. In this commentary, we frame the findings of L. A. Bartelt, A. J. Markmann, B. Nelson, J. Keys, et al. (mBio 13:e01751-22, 2022, https://doi.org/10.1128/mBio.01751-22) in the context of the normal approval process for a therapeutic product. We point out that convalescent plasma has taken all of the typical steps associated with approval for a therapeutic product. Additionally, in less than 3 years, the optimal use cases and continued utility of this product to treat COVID-19 have been defined.