Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Maternal mental health disorders and offspring asthma and allergic diseases: The role of child mental health.

BACKGROUND: Maternal psychological stress during pregnancy and postnatally has been shown to be associated with offspring atopic diseases (asthma, atopic dermatitis and allergic rhinitis). The aim of this study was to assess whether this association may be attributable to the child's own mental health disorders. METHOD: The study population included 15,092 twin children born 2002-2010 in Sweden. Questionnaire data at age 9 years was linked to national patient- and prescription registers. Maternal mental health during pregnancy and 3 years postnatally were identified from diagnosis and medication data (depression, anxiety and stress disorders). Atopic diseases in children were identified from questionnaires, diagnosis and medication data. Child mental health status (depression and anxiety) was identified from questionnaires. Three-way decomposition methods tested for mediation or interaction by child mental health disorders. RESULTS: Maternal mental health disorders were associated with most child atopic diseases including asthma aRR1.36 (95% CI 1.12, 1.60), and child mental health disorders, aRR1.73 (95% CI 1.56, 1.92). Children with mental health disorders were comorbid for atopic diseases with only asthma reaching statistical significance, aRR1.29 (95% CI 1.14, 1.47). Three-way decomposition found that mediation or interaction by child mental health disorders did not account for the mother mental health and child atopy associations except in parent-report asthma, where child mental health disorders mediated 13.4% (95% CI 2.1, 24.7) of the effect, but not for objectively defined (diagnosis and medication) asthma. CONCLUSION: The associations between maternal mental health and child asthma and allergic diseases do not appear to be attributable to child mental health disorders.

Understanding the relationship between asthma and autism spectrum disorder: a population-based family and twin study.

BACKGROUND: There is some evidence that autism spectrum disorder (ASD) frequently co-occurs with immune-mediated conditions including asthma. We aimed to explore the familial co-aggregation of ASD and asthma using different genetically informed designs. METHODS: We first examined familial co-aggregation of asthma and ASD in individuals born in Sweden from 1992 to 2007 (n = 1 569 944), including their full- and half-siblings (n = 1 704 388 and 356 544 pairs) and full cousins (n = 3 921 890 pairs), identified using Swedish register data. We then applied quantitative genetic modeling to siblings (n = 620 994 pairs) and twins who participated in the Child and Adolescent Twin Study in Sweden (n = 15 963 pairs) to estimate the contribution of genetic and environmental factors to the co-aggregation. Finally, we estimated genetic correlations between traits using linkage disequilibrium score regression (LDSC). RESULTS: We observed a within-individual association [adjusted odds ratio (OR) 1.33, 95% confidence interval (CI) 1.28-1.37] and familial co-aggregation between asthma and ASD, and the magnitude of the associations decreased as the degree of relatedness decreased (full-siblings: OR 1.44, 95% CI 1.38-1.50, maternal half-siblings: OR 1.28, 95% CI 1.18-1.39, paternal half-siblings: OR 1.05, 95% CI 0.96-1.15, full cousins: OR 1.06, 95% CI 1.03-1.09), suggesting shared familial liability. Quantitative genetic models estimated statistically significant genetic correlations between ASD traits and asthma. Using the LDSC approach, we did not find statistically significant genetic correlations between asthma and ASD (coefficients between -0.09 and 0.12). CONCLUSIONS: Using different genetically informed designs, we found some evidence of familial co-aggregation between asthma and ASD, suggesting the weak association between these disorders was influenced by shared genetics.

High-resolution integrated dynamic shimming diffusion-weighted imaging (DWI) in the assessment of rectal cancer.

OBJECTIVES: To investigate the feasibility of high-resolution integrated dynamic shimming echo planar imaging (iEPI) applied to rectal cancer. METHODS: A total of seventy-eight patients with non-mucinous rectum adenocarcinoma were enrolled in this study. Using a prototype high-resolution iEPI sequence, high-resolution single-shot EPI (sEPI) sequence, and sEPI sequence, subjective and objective assessment and apparent diffusion coefficient (ADC) value were measured for comparison. The spearman rank correlation analysis test and the receiver operating characteristic curve were performed to evaluate correlation between tumor ADC values, corresponding T stage, and differentiation degree of rectal cancer. RESULTS: The subjective assessment of the image quality (IQ) of high-resolution iEPI was rated superior to high-resolution sEPI and sEPI by both readers (p < 0.001). Signal-to-noise ratio, contrast-to-noise, and signal-intensity ratio were significantly higher in high-resolution iEPI than the other two sequences (p < 0.001). There was no significant difference of tumor ADC values among three EPI sequences in the group of low- to well-differentiated rectal cancer. An inverse correlation was noted between ADC values on three DWI sequences and pathological T stage of rectal cancer (r = - 0.693, - 0.689, - 0.640, p < 0.001). The AUC values of high-resolution iEPI, high-resolution sEPI, and sEPI in predicting well-differentiated rectal cancer were 0.910, 0.761, and 0.725 respectively. CONCLUSIONS: In conclusion, the high-resolution iEPI provided significantly higher IQ and stable ADC compared to another two sequences. High-resolution iEPI has the highest efficacy among three examined sequences in differentiation of rectal cancer with different degrees of differentiation. KEY POINTS: • High-resolution iEPI provided a significantly better IQ than high-resolution sEPI and sEPI when assessing rectal cancer. • The AUC of high-resolution sEPI was the highest among three EPI sequences in predicting well-differentiated rectal cancer.

Parental socioeconomic status and asthma in children: Using a population-based cohort and family design.

BACKGROUND: The observed association between the parental socioeconomic status (SES, measured as education/income) and asthma or wheezing in offspring may be explained by confounding of unmeasured factors (shared genes and family environment). We aimed to study the association between parental SES and asthma/wheeze using cousin comparison. METHOD: Data were collected on individuals born in Sweden 2001-2013. Parental SES (education and income) was gathered from Statistics Sweden. Asthma/wheeze was identified using national health registers. The association between parental SES at birth and incident asthma/wheeze was estimated using Cox regression also comparing differently exposed cousins. The association between parental SES at 5 years and current asthma was estimated using logistic regression. RESULTS: Included were 955,371 individuals. Mothers with compulsory school only (lowest education group) compared with those with further education (highest education group) was associated with incident asthma/wheeze below 1 year of age HRadj = 1.45 (1.38-1.52) and over 1 year of age HRadj = 1.17 (1.13-1.20). The corresponding estimates for the lowest income group were HRadj = 1.61 (1.54-1.69) and HRadj = 0.94 (0.92-0.97), respectively. In maternal cousin comparisons, the associations for asthma/wheeze over 1 year of age was HRadj = 1.21 (1.05-1.40) for compulsory school only and HRadj = 0.94 (0.84-1.07) for the lowest income group. The ORadj for current asthma at 5 years was 1.05 (1.00-1.11) for mother's compulsory school only and 0.98 (0.94-1.02) for mother's lowest income group. Results for estimates were similar for father's SES. CONCLUSION: We confirm an association between low parental SES (measured as education) and asthma/wheeze. Cousin comparison suggests that this association is not wholly due to confounding of unknown familial factors, therefore supporting a causal relationship. The relationship between parental income and asthma/wheeze is less clear. This study is important for understanding risk factors for asthma/wheeze and for future prevention strategies. Further research is warranted to investigate the possible mechanisms for association between parental education and asthma/wheeze.

Comorbidity of atopic diseases and gastro-oesophageal reflux: evidence of a shared cause.

INTRODUCTION: Gastro-oesophageal reflux disease (GERD) is the most common non-allergic comorbidity in adults with asthma; however, comorbidity with other atopic diseases such as eczema and hay fever is unclear. The objective was to assess the comorbidity of GERD with asthma and atopic diseases and to investigate possible mechanisms, including genetic and/or affective factors. METHODS: A co-twin control study harnessing 46 583 adult twins. Questionnaires on health status were linked to national patient and prescribed drug register data. Analyses tested associations of comorbidity between multiple definitions of atopic diseases (self-report and register-based) with GERD. Comparisons were made between unpaired, monozygotic (MZ) and dizygotic (DZ) twins to assess genetic liability. Affective traits (depression, anxiety and neuroticism) were added to models as possible explanatory factors. RESULTS: The risk of GERD in those with asthma was OR (odds ratio) 1.52 (95% CI 1.38, 1.68), hay fever OR 1.22 (95%CI 1.12, 1.34) and eczema OR 1.23 (95%CI 1.10, 1.38). Adjusting for affective traits completely attenuated the comorbidity associations for hay fever and eczema with GERD, and partly for asthma with GERD. Co-twin control associations attenuated suggesting a shared cause for both GERD and atopic diseases. For example, all twins adjOR 1.32 (95%CI 1.00, 1.74), 0.97 (95% CI 0.76-1.23) and 1.11 (95%CI 0.85-1.45) for self-report asthma, hay fever and eczema with GERD respectively. CONCLUSIONS: GERD is a common comorbidity in adults with asthma, hay fever and/or eczema. We found evidence for shared mechanisms suggesting common underlying causes that may involve affective traits requiring further investigation.

Paediatric asthma and non-allergic comorbidities: A review of current risk and proposed mechanisms.

It is increasingly recognized that children with asthma are at a higher risk of other non-allergic concurrent diseases than the non-asthma population. A plethora of recent research has reported on these comorbidities and progress has been made in understanding the mechanisms for comorbidity. The goal of this review was to assess the most recent evidence (2016-2021) on the extent of common comorbidities (obesity, depression and anxiety, neurodevelopmental disorders, sleep disorders and autoimmune diseases) and the latest mechanistic research, highlighting knowledge gaps requiring further investigation. We found that the majority of recent studies from around the world demonstrate that children with asthma are at an increased risk of having at least one of the studied comorbidities. A range of potential mechanisms were identified including common early life risk factors, common genetic factors, causal relationships, asthma medication and embryologic origins. Studies varied in their selection of population, asthma definition and outcome definitions. Next, steps in future studies should include using objective measures of asthma, such as lung function and immunological data, as well as investigating asthma phenotypes and endotypes. Larger complex genetic analyses are needed, including genome-wide association studies, gene expression-functional as well as pathway analyses or Mendelian randomization techniques; and identification of gene-environment interactions, such as epi-genetic studies or twin analyses, including omics and early life exposure data. Importantly, research should have relevance to clinical and public health translation including clinical practice, asthma management guidelines and intervention studies aimed at reducing comorbidities.

Effect of hydraulic retention time on the denitrification performance and metabolic mechanism of a multi-chambered bio-electrochemical system.

The effects of hydraulic retention time (HRT) on the denitrification performance of the multi-chambered bio-electrochemistry system and the metabolic mechanism of the microbial community were investigated. Results indicated that the NO3--N and NO2--N removal efficiency was up to 99.5% and 99.9%, respectively. The electricity generation performance of the system was optimum at 24 h HRT, with the maximum power density and output voltage of the fourth chamber to be 471.2 mW/m3 and 602.4 mV, respectively. With the decrease of HRT from 24 h to 8 h, the protein-like substance in extracellular polymeric substance (EPS) of granular sludge was reduced and the fluorescence intensities were weakened. Besides, the abundance of metabolism pathway was the highest at 50.0% and 49.9%, respectively, and the methane metabolism (1.8% and 2.0%, respectively) and the nitrogen metabolism (0.8% and 0.9%, respectively) in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway played important roles in providing guaranteed stability and efficient removal of organic matter and nitrogen from the system.

Intravoxel Incoherent Motion Diffusion-weighted MRI of Infiltrated Marrow for Predicting Overall Survival in Newly Diagnosed Acute Myeloid Leukemia.

Background Acute myeloid leukemia (AML) features relatively low overall survival (OS). Intravoxel incoherent motion (IVIM) diffusion-weighted MRI separates tissue microcapillary perfusion and diffusivity and may have potential for helping to assess prognosis in infiltrated marrow disease apart from solid tumor. Thus, a study of overall survival would contribute to clarifying the value of IVIM for assessing long-term prognosis in AML. Purpose To determine whether the IVIM-derived parameters of infiltrated bone marrow may be associated with OS in newly diagnosed AML. Materials and Methods This prospective study enrolled participants with newly diagnosed AML between July 2014 to March 2016 consecutively. Participants underwent MRI of the lumbar spine by using an IVIM sequence. Participant clinical characteristics and OS were collected. The median of follow-up period was 20 months (range, 1-56 months). The IVIM parameters (pseudoperfusion fraction, f; diffusion coefficient, D; and pseudodiffusion coefficient, D*) were obtained. A nonparametric log-rank test was used to identify the threshold of IVIM parameters for OS. Univariable Kaplan-Meier and multivariable Cox proportional hazards regression analyses were performed to investigate prognostic significance of possible indicators. Results Fifty-three participants (mean age, 42 years ± 17; 30 men) were evaluated. Nonparametric log-rank test results showed that the thresholds of f and D values for OS were 31.0% and 0.2 × 10-3 mm2/sec, respectively. Univariable analyses indicated that high f value (>31.0%) and low D value (≤0.2 × 10-3 mm2/sec) were associated with shorter OS (P = .003 and .01, respectively). An f value greater than 31.0% (hazard ratio, 2.4; 95% confidence interval: 1.0, 5.6; P = .046) was associated with OS, independent of clinical confounders (age, karyotype, and white blood cell counts) in a multivariable analysis. Conclusion Pseudoperfusion fraction and diffusion coefficient from intravoxel incoherent motion diffusion-weighted MRI may be viable prognosis predictors of newly diagnosed acute myeloid leukemia. © RSNA, 2020.

Early-life antibiotic use and risk of asthma and eczema: results of a discordant twin study.

RATIONALE: Early-life antibiotic use has been associated with the development of atopic diseases, but the aetiology remains unclear. To elucidate the aetiology, we used a discordant twin design to control for genetic and environmental confounding. METHODS: We conducted a retrospective cohort study in twins aged 3-10 years from the Netherlands Twin Register (NTR, n=35 365) and a replication study in twins aged 9 years from the Childhood and Adolescent Twin Study in Sweden (CATSS, n=7916). Antibiotic use was recorded at age 0-2 years. Doctor-diagnosed asthma and eczema were reported by parents when children were aged 3-12 years in both cohorts. Individuals were included in unmatched analyses and in co-twin control analyses with disease discordant twin pairs. RESULTS: Early-life antibiotic use was associated with increased risk of asthma (NTR OR 1.34, 95% CI 1.28-1.41; CATSS OR 1.45, 95% CI 1.34-1.56) and eczema (NTR OR 1.08, 95% CI 1.03-1.13; CATSS OR 1.07, 95% CI 1.01-1.14) in unmatched analyses. Co-twin analyses in monozygotic and dizygotic twin pairs showed similar results for asthma (NTR OR 1.54, 95% CI 1.20-1.98; CATSS OR 2.00, 95% CI 1.28-3.13), but opposing results for eczema in the NTR (OR 0.99, 95% CI 0.80-1.25) and the CATSS (OR 1.67, 95% CI 1.12-2.49). The risk of asthma increased for antibiotics prescribed for respiratory infections (CATSS OR 1.45, 95% CI 1.34-1.56), but not for antibiotics commonly used for urinary tract/skin infections (CATSS OR 1.02, 95% CI 0.88-1.17). CONCLUSION: Children exposed to early-life antibiotic use, particularly prescribed for respiratory infections, may be at higher risk of asthma. This risk can still be observed when correcting for genetic and environmental factors. Our results could not elucidate whether the relationship between early-life antibiotic use and eczema is confounded by familial and genetic factors.

Correlation of Intravoxel Incoherent Motion Parameters and Histological Characteristics From Infiltrated Marrow in Patients With Acute Leukemia.

BACKGROUND: An accurate and noninvasive method is of great importance to assess angiogenesis and cellularity of bone marrow in acute leukemia (AL). PURPOSE: To investigate whether the intravoxel incoherent motion (IVIM) parameters correlate with the histological characteristics of infiltrated marrow in AL patients and compare the difference between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). STUDY TYPE: Prospective. POPULATION MODEL: Forty newly diagnosed patients with AL, including 20 AML and 20 ALL. FIELD STRENGTH/SEQUENCE: 1.5T/T1 WI and IVIM. ASSESSMENT: IVIM-derived parameters (true diffusion coefficient D, pseudodiffusion coefficient D*, and perfusion fraction, f) were measured in lumbar marrow. Histopathological analyses were performed from samples of marrow biopsy. STATISTICAL TESTS: The correlations between IVIM parameters and histological parameters used the Spearman correlation test. The difference of IVIM parameters and histological parameters between ALL and AML groups used the unpaired t-test or Mann-Whitney U-test, as appropriate. RESULTS: The f was positively correlated with microvessel density (MVD) in patients with ALL, AML, and AL (r = 0.740, P = 0.006; r = 0.771, P < 0.001; and r = 0.750, P < 0.001, respectively). There were no significant correlations between D and bone marrow cellularity in the three groups (r = -0.289, P = 0.362; r = 0.281, P = 0.292; and r = 0.058, P = 0.769, respectively). D and f values of ALL were higher than that of AML group (t = 3.332, P = 0.003 and t = 2.600, P = 0.014, respectively). MVD was higher in ALL than AML (t = 2.120, P = 0.044), whereas bone marrow cellularity had no significant difference between AML and ALL (t = -0.682, P = 0.501). DATA CONCLUSION: The f value derived from IVIM in bone marrow was positively correlated with MVD, while f might be able to show a difference of vascularity between ALL and AML. Therefore, the f value can be used as an alternative imaging marker of angiogenesis in marrow of AL patients. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1720-1726.

Parental asthma and risk of autism spectrum disorder in offspring: A population and family-based case-control study.

BACKGROUND: Associations between parental asthma and prenatal exposure to asthma medications with offspring autism spectrum disorder (ASD) have been reported. However, the associations might be confounded by unmeasured (genetic and shared environmental) familial factors. OBJECTIVE: We investigated the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to ß2-agonists, other asthma medications and offspring ASD using cases and controls selected from the population as well as biological relatives with different degrees of relatedness. METHODS: We included all children (N = 1 579 263) born in Sweden 1992-2007. A nested case-control design was used to compare 22 894 ASD cases identified from the National Patient Register to (a) 228 940 age-, county- and sex-matched controls randomly selected from the population, (b) their eligible full-siblings (n = 1267), (c) half-siblings (n = 1323), (d) full-cousins (n = 11 477) and (e) half-cousins (n = 3337). Conditional logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for ASD in children differentially exposed to parental asthma or prenatal asthma medications. RESULTS: Maternal asthma was associated with increased risk of offspring ASD (OR 1.43, 95% CI 1.38-1.49); there was a weaker association for paternal asthma (OR 1.17, 95% CI 1.11-1.23). The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings (OR 1.20, 95% CI 0.80-1.81), full-cousins (OR 1.28, 95% CI 1.16-1.41) and half-cousins (OR 1.30, 95% CI 1.10-1.54), albeit with wider confidence intervals. Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD. CONCLUSIONS AND CLINICAL RELEVANCE: In this large observational study, parental asthma was associated with slightly elevated risk of ASD in offspring. More specifically, the increased risk by maternal asthma did not seem to be confounded by familial factors. There was no evidence of an association between asthma medications during pregnancy and offspring ASD.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

Agreement between asthma questionnaire and health care register data.

PURPOSE: Risk factors and consequences of asthma can be studied by using validated questionnaires. The overall objective of this study was to assess the agreement of parental-reported asthma-related questions regarding their children against Swedish health care registers. METHODS: We linked a population-based twin cohort of 27 055 children aged 9 to 12 years to the Swedish Prescribed Drug Register, National Patient Register, and the primary care register. Parent-reported asthma was obtained from questionnaires, and diagnoses and medication were retrieved from the registers. For the agreement between the questionnaire and the registers, Cohen's kappa was estimated. RESULTS: The kappa of the "reported ever asthma" against a "register-based ever asthma" was 0.69 and 0.57 between the parental-"reported doctor's diagnosis" and "register-based doctor's diagnosis." The highest agreement between "reported current asthma" and "register-based current asthma" with at least 1 dispensed medication or a diagnosis applied to different time windows was seen for an 18-month window (kappa = 0.70). CONCLUSIONS: We found that parent-reported asthma-related questions showed on average good agreement with the Swedish health care registers. This implies that in-depth questionnaires with rich information on phenotypes are suitable proxies for asthma in general and can be used for health care research purposes.

Intravoxel incoherent motion diffusion-weighted imaging of bone marrow in patients with acute myeloid leukemia: a pilot study of prognostic value.

PURPOSE: To investigate the value of intravoxel incoherent motion (IVIM) parameters in evaluation of prognosis in patients with acute myeloid leukemia (AML) before treatment. MATERIALS AND METHODS: Fifty-three patients before standard chemotherapy underwent MRI scans at 1.5 Tesla using conventional diffusion weighted imaging (DWI) and IVIM (b = 0, 10, 25, 50, 100, 200, 400, 600, 800, 1000, 1200 s/mm2 ) in the sagittal plane covering the lumbar bone marrow. The IVIM parameters (perfusion fraction [f], molecular diffusion coefficient [D], and perfusion-related D [D*] and apparent diffusion coefficient (ADC) were extracted from the bone marrow images. All patients were divided into complete remission (CR) and nonremission (NR) group according to the treatment response. RESULTS: All patients underwent the first remission induction chemotherapy, with 33 patients achieved CR and 20 patients achieved NR. The ADC values were not significant different between the two groups (P = 0.118). However, D value of CR group was significantly higher (P = 0.010), and f value of CR group was significantly lower (P = 0.021) than those of NR group. D* values had no significant differences between the two groups (P = 0.955). The D and f values were significant prognostic factors of AML after controlling for potential confounding factors (age, gender and smoking). Using receiver operator characteristic analysis, the area under the curve of D and f were 0.759 and 0.666, respectively, in evaluating prognosis of AML before treatment. CONCLUSION: There were significant differences in IVIM parameters between CR and NR patients of AML before treatment, and the D and f could play a potential role in prognosticating patients with AML. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:476-482.

Associations Between Asthma and Sensitization to Pet or Pollen Allergens in Young Swedish Twins - The STOPPA Study.

BACKGROUND: An association between childhood asthma and IgE sensitization has been established, but our understanding of the genetic and environmental contribution to it is incomplete. Our aim was to estimate the associations and dose-response relationship between asthma and sensitization to airborne allergens in Swedish 9- to 14-year-old twins. Additionally, we aimed to explore the importance of familial confounding from shared genes and environment using co-twin controls. METHODS: In the STOPPA cohort, 752 same-sex twin children were screened with Phadiatop® (Thermo Fisher Scientific; Pharmacia, Uppsala, Sweden); if positive further analysis of IgE antibodies to airborne allergens of pets (cat, horse, dog), pollens (birch, timothy, mugwort), mites, and mold were performed. The associations between asthma and airborne allergens were assessed with generalized estimating equations. The co-twin control analysis was performed by conditional logistic regression. RESULTS: Children with positive Phadiatop® had more than doubled odds of asthma (OR 2.53, 95% CI [1.74, 3.70]). Sensitization to pet allergens was associated with increased odds of asthma; for example, cat OR 4.15 (95% CI [2.67, 6.45]), with similar estimates for pollens; for example, birch OR 3.22 (95% CI [2.12, 4.91]). Associations persisted with sensitization as a categorical variable and for trend, indicating a dose-response relationship. Results remained in the co-twin analyses; for example, cat OR 4.75 (95% CI [1.62, 14.0]) and birch OR 5.00 (95% CI [1.45, 17.3]). CONCLUSION: The association between childhood asthma and sensitization to airborne allergens remains in co-twin analyses, indicating they are not due to confounding from shared environmental or genetic factors.

Towards non-conventional methods of designing register-based epidemiological studies: An application to pediatric research.

AIMS: Various epidemiological designs have been applied to investigate the causes and consequences of fetal growth restriction in register-based observational studies. This review seeks to provide an overview of several conventional designs, including cohort, case-control and more recently applied non-conventional designs such as family-based designs. We also discuss some practical points regarding the application and interpretation of family-based designs. METHODS: Definitions of each design, the study population, the exposure and the outcome measures are briefly summarised. Examples of study designs are taken from the field of low birth-weight research for illustrative purposes. Also examined are relative advantages and disadvantages of each design in terms of assumptions, potential selection and information bias, confounding and generalisability. Kinship data linkage, statistical models and result interpretation are discussed specific to family-based designs. RESULTS: When all information is retrieved from registers, there is no evident preference of the case-control design over the cohort design to estimate odds ratios. All conventional designs included in the review are prone to bias, particularly due to residual confounding. Family-based designs are able to reduce such bias and strengthen causal inference. In the field of low birth-weight research, family-based designs have been able to confirm a negative association not confounded by genetic or shared environmental factors between low birth weight and the risk of asthma. CONCLUSIONS: We conclude that there is a broader need for family-based design in observational research as evidenced by the meaningful contributions to the understanding of the potential causal association between low birth weight and subsequent outcomes.

Using fathers as a negative control exposure to test the Developmental Origins of Health and Disease Hypothesis: A case study on maternal distress and offspring asthma using Swedish register data.

BACKGROUND: Developmental Origins of Health and Disease Hypothesis (DOHaD) studies are often observational in nature and are therefore prone to biases from loss to follow-up and unmeasured confounding. Register-based studies can reduce these issues since they allow almost complete follow-up and provide information on fathers that can be used in a negative control analysis to assess the impact of unmeasured confounding. AIM: The aim of this study was to propose a causal model for testing DOHaD using paternal exposure as a negative control, and its application to maternal distress in pregnancy and offspring asthma. METHODS: A causal diagram including shared and parent-specific measured and unmeasured confounders for maternal (fetal) and paternal exposures is proposed. The case study consisted of all children born in Sweden from July 2006 to December 2008 ( n=254,150). Information about childhood asthma, parental distress and covariates was obtained from the Swedish national health registers. Associations between maternal and paternal distress during pregnancy and offspring asthma at age five years were assessed separately and with mutual adjustment for the other parent's distress measure, as well as for shared confounders. RESULTS: Maternal distress during pregnancy was associated with offspring asthma risk; mutually adjusted odds ratio (OR) (OR 1.32, 95% CI 1.23, 1.43). The mutually adjusted paternal distress-offspring asthma analysis (OR 1.05, 95% CI 0.97, 1.13) indicated no evidence for unmeasured confounding shared by the mother and father. CONCLUSIONS: Using paternal exposure in a negative control model to test the robustness of fetal programming hypotheses can be a relatively simple extension of conventional observational studies but limitations need to be considered.

Exposure to air pollution from traffic and neurodevelopmental disorders in Swedish twins.

BACKGROUND: Recent studies have reported associations between air pollution exposure and neurodevelopmental disorders in children, but the role of pre- and postnatal exposure has not been elucidated. AIM: We aimed to explore the risk for autism spectrum disorders (ASD) and attention-deficit hyperactivity disorder (ADHD) among children in relation to pre- and postnatal exposure to air pollution from road traffic. METHODS: Parents of 3,426 twins born in Stockholm during 1992-2000 were interviewed, when their children were 9 or 12 years old, for symptoms of neurodevelopmental disorders. Residence time-weighted concentrations of particulate matter with a diameter <10 µm (PM10) and nitrogen oxides (NOx) from road traffic were estimated at participants' addresses during pregnancy, the first year, and the ninth year of life using dispersion modeling, controlling for seasonal variation. Multivariate regression models were used to examine the association between air pollution exposure and neurodevelopmental outcomes, adjusting for potential confounding factors. RESULTS: No clear or consistent associations were found between air pollution exposure during any of the three time windows and any of the neurodevelopmental outcomes. For example, a 5-95% difference in exposure to NOx during pregnancy was associated with odds ratios (ORs) of 0.92 (95% confidence interval (CI): 0.44-1.96) and 0.90 (95% CI: 0.58-1.40) for ASD and ADHD respectively. A corresponding range in exposure to PM10 during pregnancy was related to ORs of 1.01 (95% CI: 0.52-1.96) and 1.00 (95% CI: 0.68-1.47) for ASD and ADHD. CONCLUSIONS: Our data do not provide support for an association between pre- or postnatal exposure to air pollution from road traffic and neurodevelopmental disorders in children.

The application of the golden-angle radial sparse parallel technique in T restaging of locally advanced rectal cancer after neoadjuvant chemoradiotherapy.

PURPOSE: To evaluate the diagnostic performance of Golden-Angle Radial Sparse Parallel (GRASP) MRI in identifying pathological stage T0-1 (ypT0-1) after neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer, compared to T2-weighted imaging (T2WI) combined with Diffusion Weighted Imaging (DWI). METHODS: In this retrospective study, 168 patients were carefully selected based on inclusion criteria that targeted individuals with biopsy-confirmed primary rectal adenocarcinoma, identified via MRI as having locally advanced disease (≥ T3 and/or positive lymph node results) prior to nCRT. Post-nCRT, all MRI images obtained after nCRT were assessed by two observers independently. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for identifying ypT0-1 based on GRASP and T2 + DWI were calculated. Multivariable regression analysis was used to explore the factors independently associated with ypT0-1 tumor. RESULTS: 45 patients out of these cases were ypT0-1, and the accuracy, sensitivity, specificity, PPV, and NPV of GRASP were higher than the T2 + DWI (88% vs 74%, 93% vs 71%, 86% vs 75%, 71% vs 52% and 97% vs 88%), the AUC in identifying ypT0-1 tumor based on GRASP was 0.90 (95% CI:0.84, 0.94), which was better than the T2 + DWI (0.73; 95% CI: 0.66, 0.80). Multivariable logistic regression analysis showed that the yT stage on GRASP scans was the only factor independently associated with ypT0-1 tumor (P < 0.001). CONCLUSION: The GRASP helped distinguish ypT0-1 tumor after nCRT and can select patients who may be suitable for local excision.