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The Hierarchical Taxonomy of Psychopathology (HiTOP) has emerged out of the quantitative approach to psychiatric nosology. This approach identifies psychopathology constructs based on patterns of co-variation among signs and symptoms. The initial HiTOP model, which was published in 2017, is based on a large literature that spans decades of research. HiTOP is a living model that undergoes revision as new data become available. Here we discuss advantages and practical considerations of using this system in psychiatric practice and research. We especially highlight limitations of HiTOP and ongoing efforts to address them. We describe differences and similarities between HiTOP and existing diagnostic systems. Next, we review the types of evidence that informed development of HiTOP, including populations in which it has been studied and data on its validity. The paper also describes how HiTOP can facilitate research on genetic and environmental causes of psychopathology as well as the search for neurobiologic mechanisms and novel treatments. Furthermore, we consider implications for public health programs and prevention of mental disorders. We also review data on clinical utility and illustrate clinical application of HiTOP. Importantly, the model is based on measures and practices that are already used widely in clinical settings. HiTOP offers a way to organize and formalize these techniques. This model already can contribute to progress in psychiatry and complement traditional nosologies. Moreover, HiTOP seeks to facilitate research on linkages between phenotypes and biological processes, which may enable construction of a system that encompasses both biomarkers and precise clinical description.
Ethical decision making has long been recognized as critical for industrial-organizational (I-O) psychologists in the variety of roles they fill in education, research, and practice. Decisions with ethical implications are not always readily apparent and often require consideration of competing concerns. The American Psychological Association (APA) Ethical Principles of Psychologists and Code of Conduct are the principles and standards to which all Society for Industrial and Organizational Psychology (SIOP) members are held accountable, and these principles serve to aid in decision making. To this end, the primary focus of this article is the presentation and application of an integrative ethical decision-making framework rooted in and inspired by empirical, philosophical, and practical considerations of professional ethics. The purpose of this framework is to provide a generalizable model that can be used to identify, evaluate, resolve, and engage in discourse about topics involving ethical issues. To demonstrate the efficacy of this general framework to contexts germane to I-O psychologists, we subsequently present and apply this framework to five scenarios, each involving an ethical situation relevant to academia, practice, or graduate education in I-O psychology. With this article, we hope to stimulate the refinement of this ethical decision-making model, illustrate its application in our profession, and, most importantly, advance conversations about ethical decision making in I-O psychology.
Diagnosis of sinus venosus defects, not infrequently associated with complex anomalous pulmonary venous drainage, may be delayed requiring multimodality imaging.
Retrospective review of all patients from February 2008 to January 2019.
Thirty-seven children were diagnosed at a median age of 4.2 years (range 0.5−15.5 years). In 32 of 37 (86%) patients, diagnosis was achieved on transthoracic echocardiography, but five patients (14%) had complex variants (four had high insertion of anomalous vein into the superior caval vein and three had multiple anomalous veins draining to different sites, two of whom had drainage of one vein into the high superior caval vein). In these five patients, the final diagnosis was achieved by multimodality imaging and intra-operative findings. The median age at surgery was 5.2 years (range 1.6−15.8 years). Thirty-one patients underwent double patch repair, four patients a Warden repair, and two patients a single-patch repair. Of the four Warden repairs, two patients had a high insertion of right-sided anomalous pulmonary vein into the superior caval vein, one patient had bilateral superior caval veins, and one patient had right lower pulmonary vein insertion into the right atrium/superior caval vein junction. There was no post-operative mortality, reoperation, residual shunt or pulmonary venous obstruction. One patient developed superior caval vein obstruction and one patient developed atrial flutter.
Complementary cardiac imaging modalities improve diagnosis of complex sinus venosus defects associated with a wide variation in the pattern of anomalous pulmonary venous connection. Nonetheless, surgical treatment is associated with excellent outcomes.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
A goosegrass [Eleusine indica (L.) Gaertn.] population uncontrolled by paraquat (R) in a vegetable production field in St. Clair County, AL, was collected in summer 2019. Research was conducted to assess the level of resistance of the suspected resistant population compared with three populations with no suspected paraquat resistance (S1, S2, and S3). Visual injury at all rating dates and biomass reduction at 28 d after treatment (DAT) of S populations occurred exponentially to increasing paraquat rates. S biotypes were injured more than R at 3 DAT, with biomass recovery at 28 DAT only occurring at rates <0.28 kg ha−1. Plant death or biomass reduction did not occur for any rate at any date for R. Paraquat rates that induced 50% or 90% injury or reduced biomass 50% or 90% compared with the non-treated (I50 or I90, respectively) ranged from 10 to 124 times higher I50 for R compared with S and 54 to 116 times higher I90 for R compared with S biotypes. These data confirm a paraquat-resistant E. indica biotype in Alabama, providing additional germplasm for study of resistance to photosystem I electron-diverting (PSI-ED) resistance mechanisms.
Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).
Materials and Methods
Patients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.
Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.
These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.
Childhood exposure to interpersonal violence (IPV) may be linked to distinct manifestations of mental illness, yet the nature of this change remains poorly understood. Network analysis can provide unique insights by contrasting the interrelatedness of symptoms underlying psychopathology across exposed and non-exposed youth, with potential clinical implications for a treatment-resistant population. We anticipated marked differences in symptom associations among IPV-exposed youth, particularly in terms of ‘hub’ symptoms holding outsized influence over the network, as well as formation and influence of communities of highly interconnected symptoms.
Participants from a population-representative sample of youth (n = 4433; ages 11–18 years) completed a comprehensive structured clinical interview assessing mental health symptoms, diagnostic status, and history of violence exposure. Network analytic methods were used to model the pattern of associations between symptoms, quantify differences across diagnosed youth with (IPV+) and without (IPV–) IPV exposure, and identify transdiagnostic ‘bridge’ symptoms linking multiple disorders.
Symptoms organized into six ‘disorder’ communities (e.g. Intrusive Thoughts/Sensations, Depression, Anxiety), that exhibited considerably greater interconnectivity in IPV+ youth. Five symptoms emerged in IPV+ youth as highly trafficked ‘bridges’ between symptom communities (11 in IPV– youth).
IPV exposure may alter mutually reinforcing symptom co-occurrence in youth, thus contributing to greater psychiatric comorbidity and treatment resistance. The presence of a condensed and unique set of bridge symptoms suggests trauma-enriched nodes which could be therapeutically targeted to improve outcomes in violence-exposed youth.
Background: Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly common in the United States and have the potential to spread widely across healthcare networks. Only a fraction of patients with CRE carriage (ie, infection or colonization) are identified by clinical cultures. Interventions to reduce CRE transmission can be explored with agent-based models (ABMs) comprised of unique agents (eg, patients) represented by a synthetic population or model-generated representation of the population. We used electronic health record data to determine CRE carriage risk, and we discuss how these results can inform CRE transmission parameters for hospitalized agents in a regional healthcare network ABM. Methods: We reviewed the laboratory data of patients admitted during July 1, 2016−June 30, 2017, to any of 7 short-term acute-care hospitals of a regional healthcare network in North Carolina (N = 118,022 admissions) to find clinically detected cases of CRE carriage. A case was defined as the first occurrence of Enterobacter spp, Escherichia coli, or Klebsiella spp resistant to any carbapenem isolated from a clinical specimen in an admitted patient. We used Poisson regression to estimate clinically detected CRE carriage risk according to variables common to data from both the electronic health records and the ABM synthetic population, including patient demographics, systemic antibiotic administration, intensive care unit stay, comorbidities, length of stay, and admitting hospital size. Results: We identified 58 (0.05%) cases of CRE carriage among all admissions. Among these cases, 30 (52%) were ≥65 years of age and 37 (64%) were female. During their admission, 47 cases (81%) were administered systemic antibiotics and 18 cases (31%) had an intensive care unit stay. Patients administered systemic antibiotics and those with an intensive care unit stay had CRE carriage risk 6.5 times (95% CI, 3.4–12.5) and 4.9 times (95% CI, 2.8–8.5) higher, respectively, than patients without these exposures (Fig. 1). Patients ≥50 years of age and those with a higher Elixhauser comorbidity index score and with longer length of stay also had increased CRE carriage risk. Conclusions: Among admissions in our dataset, CRE carriage risk was associated with systemic antibiotic exposure, intensive care unit stay, higher Elixhauser comorbidity index score, and longer length of stay. We will use these risk estimates in the ABM to inform agents’ CRE carriage status upon hospital admission and the CRE transmission parameters for short-term acute-care hospitals. We will explore CRE transmission interventions in the parameterized regional healthcare network ABM and assess the impact of CRE carriage underestimation.
Funding: This work was supported by Centers for Disease Control and Prevention (CDC) Cooperative Agreement number U01CK000527. The conclusions, findings, and opinions expressed do not necessarily reflect the official position of CDC.
At present, analysis of diet and bladder cancer (BC) is mostly based on the intake of individual foods. The examination of food combinations provides a scope to deal with the complexity and unpredictability of the diet and aims to overcome the limitations of the study of nutrients and foods in isolation. This article aims to demonstrate the usability of supervised data mining methods to extract the food groups related to BC. In order to derive key food groups associated with BC risk, we applied the data mining technique C5.0 with 10-fold cross-validation in the BLadder cancer Epidemiology and Nutritional Determinants study, including data from eighteen case–control and one nested case–cohort study, compromising 8320 BC cases out of 31 551 participants. Dietary data, on the eleven main food groups of the Eurocode 2 Core classification codebook, and relevant non-diet data (i.e. sex, age and smoking status) were available. Primarily, five key food groups were extracted; in order of importance, beverages (non-milk); grains and grain products; vegetables and vegetable products; fats, oils and their products; meats and meat products were associated with BC risk. Since these food groups are corresponded with previously proposed BC-related dietary factors, data mining seems to be a promising technique in the field of nutritional epidemiology and deserves further examination.
The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
The Murchison Widefield Array (MWA) is an open access telescope dedicated to studying the low-frequency (80–300 MHz) southern sky. Since beginning operations in mid-2013, the MWA has opened a new observational window in the southern hemisphere enabling many science areas. The driving science objectives of the original design were to observe 21 cm radiation from the Epoch of Reionisation (EoR), explore the radio time domain, perform Galactic and extragalactic surveys, and monitor solar, heliospheric, and ionospheric phenomena. All together
programs recorded 20 000 h producing 146 papers to date. In 2016, the telescope underwent a major upgrade resulting in alternating compact and extended configurations. Other upgrades, including digital back-ends and a rapid-response triggering system, have been developed since the original array was commissioned. In this paper, we review the major results from the prior operation of the MWA and then discuss the new science paths enabled by the improved capabilities. We group these science opportunities by the four original science themes but also include ideas for directions outside these categories.
Polygenic scores (PGS) are widely used to characterize genetic liability for heritable mental disorders, including attention-deficit/hyperactivity disorder (ADHD). However, little is known about the effects of a low burden of genetic liability for ADHD, including whether this functions as a low risk or protective factor for ADHD and related functional outcomes in later life. The current study examines the association of low ADHD PGS and functional outcomes in adulthood.
Participants were from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) (N = 7088; mean age = 29, s.d. = 1.74). ADHD PGS was computed from an existing genome-wide association study, and adult functional outcomes, including cognition, educational attainment, mental health, and physical health were assessed during in-home interviews.
Individuals at the lowest end of the ADHD PGS distribution (i.e. lowest 20th percentile) had the lowest probabilities of ADHD, exhibiting a 17–19% reduction in risk for ADHD relative to the observed 8.3% prevalence rate of ADHD in Add Health. Furthermore, individuals with low ADHD PGS had higher cognitive performance, greater levels of educational attainment, and lower BMI relative to individuals representing the rest of the ADHD PGS distribution, including those who were in the medium and high-PGS groups.
Findings indicate that psychiatric PGS likely capture far more than just the risk and the absence of risk for a psychiatric outcome; where one lies along the PGS distribution may predict diverging functional consequences, for better and for worse.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
African American youths are overrepresented in the American juvenile justice system relative to Caucasians. Yet, research on antisocial behaviors (ASB) has focused on predominantly Caucasian populations. Furthermore, relatively little is known about how environmental factors, such as supportive parenting (e.g., how close adolescents feel to their parent) and school connectedness (e.g., how supported adolescents feel at school), affect trajectories of ASB in Caucasians versus African Americans. This study mapped developmental trajectories of ASB in Caucasians (n = 10,764) and African Americans (n = 4,091) separately, using four waves of data from the National Longitudinal Study of Adolescent to Adult Health. We then examined supportive parenting and school connectedness on the trajectories of ASB. Four trajectories of ASB were identified for both Caucasians and African Americans: negligible, adolescence-peaked, low-persistence, and high-persistence ASB, although prevalence rates differed by racial-ethnic status. Supportive parenting reduced the risk of membership into the adolescence-peaked trajectory for both Caucasians and African Americans. However, school connectedness was less protective for African Americans than for Caucasians because it only predicted a lower risk of adolescence-peaked membership for African Americans. Findings may reflect the complex social dynamics between race and schools in the development of ASB.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.