The Effects of Birth Order and Birth Interval on the Phenotypic Expression of Autism Spectrum Disorder

A rise in the prevalence of diagnosed cases of autism spectrum disorder (ASD) has been reported in several studies in recent years. While this rise in ASD prevalence is at least partially related to increased awareness and broadened diagnostic criteria, the role of environmental factors cannot be ruled out, especially considering that the cause of most cases of ASD remains unknown. The study of families with multiple affected children can provide clues about ASD etiology. While the majority of research on ASD multiplex families has focused on identifying genetic anomalies that may underlie the disorder, the study of symptom severity across ASD birth order may provide evidence for environmental factors in ASD. We compared social and cognitive measures of behavior between over 300 first and second affected siblings within multiplex autism families obtained from the Autism Genetic Resource Exchange dataset. Measures included nonverbal IQ assessed with the Ravens Colored Progressive Matrices, verbal IQ assessed with the Peabody Picture Vocabulary Test, and autism severity assessed with the Social Responsiveness Scale (SRS), an instrument established as a quantitative measure of autism. The results indicated that females were more severely impacted by ASD than males, especially first affected siblings. When first and second affected siblings were compared, significant declines in nonverbal and verbal IQ scores were observed. In addition, SRS results demonstrated a significant increase in autism severity between first and second affected siblings consistent with an overall decline in function as indicated by the IQ data. These results remained significant after controlling for the age and sex of the siblings. Surprisingly, the SRS scores were found to only be significant when the age difference between siblings was less than 2 years. These results suggest that some cases of ASD are influenced by a dosage effect involving unknown epigenetic, environmental, and/or immunological factors.     

Low Birth Weight and Normal Birth Weight Newborns of Kolkata, India: Comparison of Some Maternal Risk Factors

This study compared several maternal risk factors of low birth weight (LBW) between 204 normal birth weight (NBW) and 133 LBW newborns from Kolkata, India. Based on their birth weight (BW), newborns were classified as LBW (BW < 2.5 kg) and NBW (BW ≥ 2.5 kg). Results revealed that means for maternal age (MA, p < 0.05), gestational age (GA, p < 0.01), hemoglobin (Hb) concentration (p < 0.05), and per capita daily income (PCDI, p < 0.05) were significantly higher among mothers of NBW. Correlation analyses revealed that MA (r = 0.119, p < 0.05), GA (r = 0.583, p < 0.01), PCDI (r = 0.118, p < 0.05), and Hb (r = 0.138, p < 0.05) were significantly positively correlated with BW; PCDI was also significantly positively correlated (r = 0.142, p < 0.01) with Hb. Stepwise regression analyses with BW as the dependent variable revealed that GA (t = 7.915, p < 0.001) and Hb (t = 2.057, p < 0.05) were the most important predictive variables. The effect of Hb, independent of GA, was statistically significant (change in F = 4.231, p < 0.05). Because GA is not modifiable in pregnant women, there is a need to increase Hb levels among pregnant mothers. Most importantly, appropriately targeted preventive strategies, including iron supplementation, need to be implemented for health promotion.     

Birth Order, Age, and Hunting Success in the Canadian Arctic

What explains variation in hunting success? This paper examines foraging success among Inuit hunters, paying particular attention to factors that account for differential returns in hunting. Although there are several possibilities for explaining hunting success, this study finds that birth order and age are important predictors of foraging returns. Furthermore, data on food sharing suggests that birth order has important effects on the distribution of food. That is, early-born hunters not only produce more food, they give much of that food to their parents, who then distribute it to the hunter’s younger siblings. These findings are discussed within the context of local resource enhancement and the value of early-born sons to Inuit parents.     

Contextual Risk Factors for Low Birth Weight: A Multilevel Analysis

Background

Low birth weight (LBW) remains to be a leading cause of neonatal death and a major contributor to infant and under-five mortality. Its prevalence has not declined in the last decade in sub-Saharan Africa (SSA) and Asia. Some individual level factors have been identified as risk factors for LBW but knowledge is limited on contextual risk factors for LBW especially in SSA.

Methods

Contextual risk factors for LBW in Ghana were identified by performing multivariable multilevel logistic regression analysis of 6,900 mothers dwelling in 412 communities that participated in the 2003 and 2008 Demographic and Health Surveys in Ghana.

Results

Contextual-level factors were significantly associated with LBW: Being a rural dweller increased the likelihood of having a LBW infant by 43% (OR 1.43; 95% CI 1.01–2.01; P-value <0.05) while living in poverty-concentrated communities increased the risk of having a LBW infant twofold (OR 2.16; 95% CI 1.29–3.61; P-value <0.01). In neighbourhoods with a high coverage of safe water supply the odds of having a LBW infant reduced by 28% (OR 0.74; 95% CI 0.57–0.96; P-value <0.05).

Conclusion

This study showed contextual risk factors to have independent effects on the prevalence of LBW infants. Being a rural dweller, living in a community with a high concentration of poverty and a low coverage of safe water supply were found to increase the prevalence of LBW infants. Implementing appropriate community-based intervention programmes will likely reduce the occurrence of LBW infants.     

Framingham Stroke Risk Profile and poor cognitive function: a population-based study

Background  

The relationship between stroke risk and cognitive function has not previously been examined in a large community living sample other than the Framingham cohort. The objective of this study was to examine the relationship between 10-year risk for incident stroke and cognitive function in a large population-based sample.     

Correlation of Age and Birth Order of Parents with Chromosomal Anomalies in Children*

One hundred children with suspected congenital and/or malformation and their parents who reported to SAT hospital, Medical College, Trivandrum, India formed the test group. Fifty children with no obvious anomalies or abnormalities and their parents formed the control group. The criteria for selection of the control was (1) the maternal age at delivery was below 30 years and (2) the parents belong to first or second birth order. The chromosomal analysis was carried out in all the subjects using peripheral blood lymphocyte microculture to investigate any constitutional chromosomal markers and quantitate the mutagen (bleomycin) sensitivity of the chromosomes. All the subjects were evaluated clinically and a complete family history was recorded. Chromosome anomalies were noted in 41 out of 100 children and in 4 out of 200 parents of the test group. No constitutional aberrations were seen either in the parents or in the children of the control group. Bleomycin sensitivity study revealed a high b/c value in 35 children (24 hypersensitive and 11 sensitive) of the test group whereas in the control group the b/c values were low denoting hyposensitivity and very good DNA repair mechanism. This study reveals that the incidence of chromosome aberrations is higher when the age and birth order of parents are higher. A direct correlation was noted with parental order and b/c value. This was also true with the parental age and birth defects.     

Methodological Approaches to Evaluate Teratogenic Risk Using Birth Defect Registries: Advantages and Disadvantages

Background

Different approaches have been used in case-control studies to estimate maternal exposure to medications and the risk of birth defects. However, the performance of these approaches and how they affect the odds ratio (OR) estimates have not been evaluated using birth-defect surveillance programmes. The aim of this study was to evaluate the scope and limitations of three case-control approaches to assess the teratogenic risk of birth defects in mothers exposed to antiepileptic medications, insulin, or acetaminophen.

Methodology/Principal Findings

We studied 110,814 non-malformed newborns and 58,514 live newborns with birth defects registered by the Latin American Collaborative Study of Congenital Anomalies (ECLAMC) between 1967 and 2008. Four controls were randomly selected for each case in the same hospital and period, and three different control groups were used: non-malformed newborns (HEALTHY), malformed newborns (SICK), and a subgroup of SICK, only-exposed cases (OECA). Associations were evaluated using OR and Pearson''s chi-square (P<0.01). There were no concordance correlations between the HEALTHY and OECA designs, and the average OR differences ranged from 3.0 to 11.5 for the three evaluated medicines. The overestimations observed for HEALTHY design were increased as higher OR values were given, with a high and statistically significant correlation between the difference and the mean. On the contrary, the concordance correlations obtained between the SICK and OECA designs were quite good, with no significant differences in the average risks.

Conclusions

The HEALTHY design estimates the true population OR, but shows a high rate of false-positive results presumably caused by differential misclassification bias. This bias decreases with the increase of the proportion of exposed controls. SICK and OECA odds ratios cannot be considered a direct estimate of the true population OR except under certain conditions. However, the SICK and OECA designs could provide practical information to generate hypotheses about potential teratogens.     

Cancer Risk in Children and Adolescents with Birth Defects: A Population-Based Cohort Study

Objective

Birth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects.

Methods and Findings

This retrospective, statewide, population-based, cohort study was conducted in three US states (Utah, Arizona, Iowa). A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state’s births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold (95% CI, 2.3 to 3.7) in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus.

Conclusion

Children with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research.     

Birth Weight and Risk of Adiposity among Adult Inuit in Greenland

Objective

The Inuit population in Greenland has undergone rapid socioeconomic and nutritional changes simultaneously with an increasing prevalence of obesity. Therefore, the objective was to examine fetal programming as part of the aetiology of obesity among Inuit in Greenland by investigating the association between birth weight and measures of body composition and fat distribution in adulthood.

Methods

The study was based on cross-sectional data from a total of 1,473 adults aged 18–61 years in two population-based surveys conducted in Greenland between 1999–2001 and 2005–2010. Information on birth weight was collected from birth records. Adiposity was assessed by anthropometry, fat mass index (FMI), fat-free mass index (FFMI), and visceral (VAT) and subcutaneous adipose tissue (SAT) estimated by ultrasound. The associations to birth weight were analyzed using linear regression models and quadratic splines. Analyses were stratified by sex, and adjusted for age, birthplace, ancestry and family history of obesity.

Results

Spline analyses showed linear relations between birth weight and adult adiposity. In multiple regression analyses, birth weight was positively associated with BMI, waist circumference, FMI, FFMI and SAT with generally weaker associations among women compared to men. Birth weight was only associated with VAT after additional adjustment for waist circumference and appeared to be specific and inverse for men only.

Conclusions

Higher birth weight among Inuit was associated with adiposity in adulthood. More studies are needed to explore a potential inverse association between birth size and VAT.     

Trajectories of Sensory Over-Responsivity from Early to Middle Childhood: Birth and Temperament Risk Factors

Sensory over-responsivity, a subtype of sensory modulation disorder, is characterized by extreme negative reactions to normative sensory experiences. These over-reactions can interfere with daily activities and cause stress to children and their families. The etiology and developmental course of sensory over-responsivity is still largely unknown. We measured tactile and auditory over-responsivity in a population-based, typically developing sample of twins (N=978) at age two years via a caregiver report temperament questionnaire and again at age seven years via a sensory over-responsivity symptom inventory. Participating twins were treated as singletons although all analyses controlled for clustering within families. Children were divided into four trajectory groups based on risk status at both ages: low symptom (N=768), remitted (N=75), late-onset (N=112), and chronic (N=24). A subset of children who screened positive for SOR in toddlerhood (N = 102) took part in a pilot study focused on sensory over-responsivity at four years of age. Children in the chronic group had more severe symptoms of sensory sensitivity at age four years, including more motion sensitivity, than the other trajectory groups. Children in the chronic group had a younger gestational age and were more likely to be low birth-weight than the low symptom group. Differences between remitted and late-onset groups and the low-symptoms group were inconsistent across measures. Sensory over-responsivity was modestly correlated across ages (r = .22 for tactile over-responsivity and r = .11 for auditory over-responsivity), but symptoms were more stable among children born prematurely or who had more fearful and less soothable temperaments. A clear implication is that assessment over development may be necessary for a valid sensory processing disorder diagnosis, and a speculative implication is that sensory over-responsivity symptoms may be etiologically heterogeneous, with different causes of transient and stable symptoms.     

Association between Birth Order and Emergency Room Visits and Acute Hospital Admissions following Pediatric Vaccination: A Self-Controlled Study

Objective

We investigated the association between a child''s birth order and emergency room (ER) visits and hospital admissions following 2-,4-,6- and 12-month pediatric vaccinations.

Methods

We included all children born in Ontario between April 1^st, 2006 and March 31^st, 2009 who received a qualifying vaccination. We identified vaccinations, ER visits and admissions using health administrative data housed at the Institute for Clinical Evaluative Sciences. We used the self-controlled case series design to compare the relative incidence (RI) of events among 1^st-born and later-born children using relative incidence ratios (RIR).

Results

For the 2-month vaccination, the RIR for 1^st-borns versus later-born children was 1.37 (95% CI: 1.19–1.57), which translates to 112 additional events/100,000 vaccinated. For the 4-month vaccination, the RIR for 1^st-borns vs. later-borns was 1.70 (95% CI: 1.45–1.99), representing 157 additional events/100,000 vaccinated. At 6 months, the RIR for 1^st vs. later-borns was 1.27 (95% CI: 1.09–1.48), or 77 excess events/100,000 vaccinated. At the 12-month vaccination, the RIR was 1.11 (95% CI: 1.02–1.21), or 249 excess events/100,000 vaccinated.

Conclusions

Birth order is associated with increased incidence of ER visits and hospitalizations following vaccination in infancy. 1^st-born children had significantly higher relative incidence of events compared to later-born children.     

Associations Between Season of Birth and the Risk of Lung Cancer: Epidemiological Findings From Hungary

Lung cancer is the leading cause of cancer deaths worldwide. Both incidence and mortality of lung cancer are especially high in Hungary. Several investigations suggested recently that month of birth (MOB) is associated with the risks of several nonmalignant disorders as well as some malignant disorders. Only a few studies investigated previously the association between MOB and risk of lung cancer, but they provided inconsistent results. We, therefore, decided to investigate this issue in a large sample of individuals who died from lung cancer. Accordingly, we determined the MOB-associated risk of death by lung cancer between the years 1970 and 2009 among all individuals born in Hungary between 1925 and 1934. The final sample included about two million people. A total of 61,904 deaths by lung cancer occurred in this sample during the period investigated. Using analysis of variance (ANOVA), we did not find significant association between MOB and risk of lung cancer death, either in the whole population investigated (F?=?1.492; p?=?.145) or in the female subpopulation (F?=?1.535; p?=?.129). However, those males born in late spring (May–June) had a lower risk of lung cancer development (F?=?2.577; p?=?.006). Results of the Edwards test also did not suggest consistent association between MOB and risk of lung cancer death in the whole investigated period (1925–1934) in any populations (i.e., whole population or male and female subpopulations). In conclusion, we did not find significant association between MOB and risk of lung cancer in our total sample (although results alluded to a weak association between MOB and risk of lung cancer development among males). The possible associations between MOB and the risk of lung cancer development (or smoking) would require confirmation (or refutation) in large studies from other populations. (Author correspondence: dome_peter@yahoo.co.uk)     

Bootstrap and Second‐Order Tests of Risk Difference

Summary Clinical trials data often come in the form of low‐dimensional tables of small counts. Standard approximate tests such as score and likelihood ratio tests are imperfect in several respects. First, they can give quite different answers from the same data. Second, the actual type‐1 error can differ significantly from nominal, even for quite large sample sizes. Third, exact inferences based on these can be strongly nonmonotonic functions of the null parameter and lead to confidence sets that are discontiguous. There are two modern approaches to small sample inference. One is to use so‐called higher order asymptotics ( Reid, 2003 , Annal of Statistics 31 , 1695–1731) to provide an explicit adjustment to the likelihood ratio statistic. The theory for this is complex but the statistic is quick to compute. The second approach is to perform an exact calculation of significance assuming the nuisance parameters equal their null estimate ( Lee and Young, 2005 , Statistic and Probability Letters 71 , 143–153), which is a kind of parametric bootstrap. The purpose of this article is to explain and evaluate these two methods, for testing whether a difference in probabilities p₂? p₁ exceeds a prechosen noninferiority margin δ₀ . On the basis of an extensive numerical study, we recommend bootstrap P‐values as superior to all other alternatives. First, they produce practically identical answers regardless of the basic test statistic chosen. Second, they have excellent size accuracy and higher power. Third, they vary much less erratically with the null parameter value δ₀ .     

Decreasing Birth Weight Is Associated with Adverse Metabolic Profile and Lower Stature in Childhood and Adolescence

Objective

We aimed to evaluate the association of birth weight SDS with insulin resistance, blood pressure, and auxology in children and adolescents born 23–42 weeks of gestation.

Methods

We studied 143 singleton children and adolescents aged 9.3 ± 3.3 years (range 2.0–17.9 years). Clinical assessments included insulin resistance measured by HOMA2-IR, auxology, and blood pressure from sphygmomanometer measurements. Continuous associations were examined, and stratified analyses carried out. For the latter, participants were divided into those of below-average birth weight (BABW, <0 SDS) and above-average birth weight (AABW, ≥0 SDS).

Results

Irrespective of gestational age, lower birth weight SDS was associated with progressively greater HOMA2-IR (p<0.0001) and higher fasting insulin concentrations (p<0.0001). Decreasing birth weight SDS was associated with higher systolic (p = 0.011) and diastolic (p = 0.006) blood pressure. Lower birth weight SDS was also associated with decreasing stature (p<0.010). The BABW group was ~40% more insulin resistant than AABW participants (p = 0.004), with the former also displaying fasting insulin concentrations 37% higher (p = 0.004). BABW participants were 0.54 SDS shorter than those of higher birth weight (p = 0.002). On average, BABW participants had not met their genetic potential, tending to be shorter than their parents (p = 0.065). As a result, when corrected for parents'' heights, BABW participants were 0.62 SDS shorter than those born of higher birth weight (p = 0.001). Sub-group analyses on participants born appropriate-for-gestational-age (n = 128) showed that associations of birth weight SDS with both insulin resistance and stature remained (although attenuated).

Conclusion

Decreasing birth weight SDS (even within the normal range) is associated with adverse metabolic profile and lower stature in children and adolescents.     

HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1^∗01:02-DQB1^∗06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1^∗01:03-DPB1^∗04:02 (DP0402; odds ratio [OR] = 0.51 [0.38–0.67], p = 1.01 × 10⁻⁶) and HLA-DPA1^∗01:03-DPB1^∗04:01 (DP0401; OR = 0.61 [0.47–0.80], p = 2.07 × 10⁻⁴) and predisposing effects of HLA-DPB1^∗05:01 in Asians (OR = 1.76 [1.34–2.31], p = 4.71 × 10⁻⁰⁵). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38–0.55] p = 8.99 × 10⁻¹⁷) and DP0501 (OR = 1.38 [1.18–1.61], p = 7.11 × 10⁻⁵). HLA-class-II-independent associations with HLA-A^∗11:01 (OR = 1.32 [1.13–1.54], p = 4.92 × 10⁻⁴), HLA-B^∗35:03 (OR = 1.96 [1.41–2.70], p = 5.14 × 10⁻⁵), and HLA-B^∗51:01 (OR = 1.49 [1.25–1.78], p = 1.09 × 10⁻⁵) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.     

Risk factors for birth defects: data from the Atlanta Birth Defects Case-Control Study

The Atlanta Birth Defects Case-Control Study data comprises information obtained from interviews with parents of 4,900 babies born with major birth defects and with the parents of 3,000 babies born without defects. The source of cases is the Centers for Disease Control's Metropolitan Atlanta Congenital Defects program; the case-control study is population-based. Birth defects are classified into 92 groups and cross-tabulated by 105 exposure/risk factor variables; data from selected cross-tabulations are presented. The associations of each of the 105 exposure variables with all types of defects combined are presented, as are the associations of each of the 92 defect groups with the specific exposure variable, maternal diabetes. These data can be used to evaluate hypotheses arising from other sources, and for the purpose of "generating" hypotheses. The data describing all 92 x 105 cross-tabulations are available to other investigators on floppy disk; write to Chief, Birth Defects and Genetic Diseases Branch, Centers for Disease Control, Atlanta, Georgia 30333.