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1.  Accuracy of Phenotyping of Autistic Children Based on Internet Implemented Parent Report 
While strong familial evidence supports a substantial genetic contribution to the etiology of autism spectrum disorders (ASD), specific genetic abnormalities have been identified in only a small minority of all cases. In order to comprehensively delineate the genetic components of autism including the identification of rare and common variants, overall sample sizes an order of magnitude larger than those currently under study are critically needed. This will require rapid and scalable subject assessment paradigms that obviate clinic-based time-intensive behavioral phenotyping, which is a rate-limiting step. Here, we test the accuracy of a web-based approach to autism phenotyping implemented within the Interactive Autism Network (IAN). Families who were registered with the IAN and resided near one of the three study sites were eligible for the study. One hundred seven children ascertained from this pool who were verbal, age 4–17 years, and had Social Communication Questionnaire (SCQ) scores ≥12 (a profile that characterizes a majority of ASD -affected children in IAN) underwent a clinical confirmation battery. One hundred five of the 107 children were ASD positive (98%) by clinician’s best estimate. One hundred four of these individuals (99%) were ASD positive by developmental history using the Autism Diagnostic Interview-Revised (ADI-R) and 97 (93%) were positive for ASD by developmental history and direct observational assessment (Autism Diagnostic Observational Schedule or expert clinician observation). These data support the reliability and feasibility of the IAN-implemented parent-report paradigms for the ascertainment of clinical ASD for large-scale genetic research.
doi:10.1002/ajmg.b.31103
PMCID: PMC4311721  PMID: 20552678
autism; ASD; sample size; genetic studies; rapid phenotyping paradigm
2.  Survey non-response in an internet-mediated, longitudinal autism research study 
Objective
To evaluate non-response rates to follow-up online surveys using a prospective cohort of parents raising at least one child with an autism spectrum disorder. A secondary objective was to investigate predictors of non-response over time.
Materials and Methods
Data were collected from a US-based online research database, the Interactive Autism Network (IAN). A total of 19 497 youths, aged 1.9–19 years (mean 9 years, SD 3.94), were included in the present study. Response to three follow-up surveys, solicited from parents after baseline enrollment, served as the outcome measures. Multivariate binary logistic regression models were then used to examine predictors of non-response.
Results
31 216 survey instances were examined, of which 8772 or 28.1% were partly or completely responded to. Results from the multivariate model found non-response of baseline surveys (OR 28.0), years since enrollment in the online protocol (OR 2.06), and numerous sociodemographic characteristics were associated with non-response to follow-up surveys (all p<0.05).
Discussion
Consistent with the current literature, response rates to online surveys were somewhat low. While many demographic characteristics were associated with non-response, time since registration and participation at baseline played the greatest role in predicting follow-up survey non-response.
Conclusion
An important hazard to the generalizability of findings from research is non-response bias; however, little is known about this problem in longitudinal internet-mediated research (IMR). This study sheds new light on important predictors of longitudinal response rates that should be considered before launching a prospective IMR study.
doi:10.1136/amiajnl-2012-000863
PMCID: PMC3384126  PMID: 22539079
ASD; autism; decision modeling; education; informatics; internet-mediated research; online survey research; public health informatics; survey non-response
3.  Validation of Proposed DSM-5 Criteria for Autism Spectrum Disorder 
Objective
The primary aim of the present study was to evaluate the validity of proposed DSM-5 criteria for Autism Spectrum Disorder (ASD).
Method
We analyzed symptoms from 14,744 siblings (8,911 ASD; 5,863 non-ASD) included in a national registry, the Interactive Autism Network. Youth aged 2–18 were included if at least one child in the family was diagnosed with ASD. Caregivers reported symptoms using the Social Responsiveness Scale and the Social Communication Questionnaire. The structure of autism symptoms was examined using latent variable models that included categories, dimensions, or hybrid models specifying categories and sub-dimensions. Diagnostic efficiency statistics evaluated the proposed DSM-5 algorithm in identifying ASD.
Results
A hybrid model that included both a category (ASD vs. non-ASD) and two symptom dimensions (social communication/interaction and restricted/repetitive behaviors) was more parsimonious than all other models and replicated across measures and sub-samples. Empirical classifications from this hybrid model closely mirrored clinical ASD diagnoses (90% overlap), implying a broad ASD category distinct from non-ASD. DSM-5 criteria had superior specificity relative to DSM-IV-TR criteria (.97 vs. .86), however sensitivity was lower (.81 vs. .95). Relaxing DSM-5 criteria by requiring one less symptom criterion increased sensitivity (.93 vs. .81), with minimal reduction in specificity (.95 vs. .97).
Conclusions
Results supported the validity of proposed DSM-5 criteria for ASD as provided in Phase I field trials criteria. Increased specificity of DSM-5 relative to DSM-IV-TR may reduce false positive diagnoses, a particularly relevant consideration for low base rate clinical settings. Phase II testing of DSM-5 should consider a relaxed algorithm, without which as many as 12% of ASD-affected individuals, particularly females, will be missed. Relaxed DSM-5 criteria may improve identification of ASD, decreasing societal costs through appropriate early diagnosis and maximizing intervention resources.
doi:10.1016/j.jaac.2011.09.021
PMCID: PMC3244681  PMID: 22176937
Autism Spectrum Disorder; diagnosis; factor analysis; latent class; factor mixture
4.  Mood Disorders in Mothers of Children on the Autism Spectrum Are Associated with Higher Functioning Autism 
Autism Research and Treatment  2012;2012:435646.
Mood disorders occur more frequently in family members of individuals with autism spectrum disorders (ASD) than in the general population. There may be associations between maternal mood disorder history patterns and specific ASD phenotypes. We therefore examined the relationship between maternal mood disorders and child autism spectrum disorders in 998 mother-child dyads enrolled in a national online autism registry and database. Mothers of children with ASD completed online questionnaires addressing their child's ASD as well as their own mood disorder history. In multivariate logistic regression models of ASD diagnoses, the odds of an Asperger disorder versus autistic disorder diagnosis were higher among those children whose mothers had a lifetime history of bipolar disorder (OR 2.11, CI 1.20, 3.69) or depression (OR 1.62, CI 1.19, 2.19). Further, maternal mood disorder onset before first pregnancy was associated with higher odds (OR 2.35, CI 1.48, 3.73) of an Asperger versus autism diagnosis among this sample of children with ASD. These data suggest that differences in maternal mood disorder history may be associated with ASD phenotype in offspring.
doi:10.1155/2012/435646
PMCID: PMC3426171  PMID: 22934172
5.  Parent Report of Community Psychiatric Comorbid Diagnoses in Autism Spectrum Disorders 
Autism Research and Treatment  2011;2011:405849.
We used a national online registry to examine variation in cumulative prevalence of community diagnosis of psychiatric comorbidity in 4343 children with autism spectrum disorders (ASD). Adjusted multivariate logistic regression models compared influence of individual, family, and geographic factors on cumulative prevalence of parent-reported anxiety disorder, depression, bipolar disorder, and attention deficit/hyperactivity disorder or attention deficit disorder. Adjusted odds of community-assigned lifetime psychiatric comorbidity were significantly higher with each additional year of life, with increasing autism severity, and with Asperger syndrome and pervasive developmental disorder—not otherwise specified compared with autistic disorder. Overall, in this largest study of parent-reported community diagnoses of psychiatric comorbidity, gender, autistic regression, autism severity, and type of ASD all emerged as significant factors correlating with cumulative prevalence. These findings could suggest both underlying trends in actual comorbidity as well as variation in community interpretation and application of comorbid diagnoses in ASD.
doi:10.1155/2011/405849
PMCID: PMC3420588  PMID: 22937248
6.  Factors Affecting Age at Initial Autism Spectrum Disorder Diagnosis in a National Survey 
Autism Research and Treatment  2011;2011:874619.
Entry into early intervention depends on both age of first parent concern (AOC) and age at initial autism spectrum disorder (ASD) diagnosis (AOD). Using data collected from a national online registry from 6214 children diagnosed with an ASD between 1994 and 2010 in the US, we analyzed the effect of individual, family, and geographic covariates on AOC and AOD in a multivariate linear regression model with random effects. Overall, no single modifiable factor associated with AOC or AOD emerged but cumulative variation in certain individual- and family-based features, as well as some geographic factors, all contribute to AOC and AOD variation. A multipronged strategy is needed for targeted education and awareness campaigns to maximize outcomes and decrease disparities in ASD care.
doi:10.1155/2011/874619
PMCID: PMC3420379  PMID: 22937257
7.  Nosocomial Sepsis Risk Score for Preterm Infants in Low-resource Settings 
Journal of Tropical Pediatrics  2009;56(2):82-89.
Sepsis is a leading cause of mortality for neonates in developing countries; however, little research has focused on clinical predictors of nosocomial infection of preterm neonates in the low-resource setting. We sought to validate the only existing feasible score introduced by Singh et al. in 2003 and to create an improved score. In a secondary analysis of daily evaluations of 497 neonates ≤33 weeks gestational age admitted to a tertiary care NICU in Dhaka, Bangladesh, we tested the Singh score and then constructed and internally validated our own bedside predictive score. The Singh score had low sensitivity of 56.6% but good positive predictive value (PPV) of 78.1% in our sample. Our five-sign model requiring at least one clinical sign of infection (apnea, hepatomegaly, jaundice, lethargy and pallor) had an area under the receiver operating characteristic of 0.70, sensitivity of 77.1%, and PPV of 64.9%. Our clinical sepsis score is the first bedside clinical screen exclusively for hospitalized, very premature neonates in a low-resource setting, and warrants external validation.
doi:10.1093/tropej/fmp061
PMCID: PMC3115678  PMID: 19622712
neonate; sepsis; prematurity; very low birth-weight; developing countries; nosocomial
8.  Sibling recurrence and the genetic epidemiology of autism 
The American journal of psychiatry  2010;167(11):1349-1356.
Objective
Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings.
Method
We report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register who met the criteria of having at least one child clinically-affected by an autism spectrum disorder (ASD) and at least one full biological sibling.
Results
The occurrence of a traditionally-defined ASD in an additional child occurred in 10.9% of the families. An additional 20% of non-ASD-affected siblings had a history of language delay, half of whom had exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale (SRS) supported previously-reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multiple-incidence families, and a relative absence of quantitative autistic traits among siblings in single-incidence autism families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts.
Conclusions
These data suggest that, depending on how it is defined, sibling recurrence in ASD may exceed previously-published estimates, and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism, and advance current understanding of the genetic epidemiology of autism.
doi:10.1176/appi.ajp.2010.09101470
PMCID: PMC2970737  PMID: 20889652
Genetics; Pervasive Developmental Disorder; Language; Broader Autism Phenotype
9.  Extended-interval Dosing of Gentamicin for Treatment of Neonatal Sepsis in Developed and Developing Countries 
Serious bacterial infections are the single most important cause of neonatal mortality in developing countries. Case-fatality rates for neonatal sepsis in developing countries are high, partly because of inadequate administration of necessary antibiotics. For the treatment of neonatal sepsis in resource-poor, high-mortality settings in developing countries where most neonatal deaths occur, simplified treatment regimens are needed. Recommended therapy for neonatal sepsis includes gentamicin, a parenteral aminoglycoside antibiotic, which has excellent activity against gram-negative bacteria, in combination with an antimicrobial with potent gram-positive activity. Traditionally, gentamicin has been administered 2–3 times daily. However, recent evidence suggests that extended-interval (i.e. ≥24 hours) dosing may be applicable to neonates. This review examines the available data from randomized and non-randomized studies of extended-interval dosing of gentamicin in neonates from both developed and developing countries. Available data on the use of gentamicin among neonates suggest that extended dosing intervals and higher doses (>4 mg/kg) confer a favourable pharmacokinetic profile, the potential for enhanced clinical efficacy and decreased toxicity at reduced cost. In conclusion, the following simplified weight-based dosing regimen for the treatment of serious neonatal infections in developing countries is recommended: 13.5 mg (absolute dose) every 24 hours for neonates of ≥2,500 g, 10 mg every 24 hours for neonates of 2,000–2,499 g, and 10 mg every 48 hours for neonates of <2,000 g.
PMCID: PMC2740664  PMID: 18686550
Developing countries; Drug therapy; Gentamicin; Infant, Newborn; Pharmacokinetics; Review literature; Sepsis
10.  Chloramphenicol versus ampicillin plus gentamicin for community acquired very severe pneumonia among children aged 2-59 months in low resource settings: multicentre randomised controlled trial (SPEAR study) 
BMJ : British Medical Journal  2008;336(7635):80-84.
Objective To evaluate whether five days’ treatment with injectable ampicillin plus gentamicin compared with chloramphenicol reduces treatment failure in children aged 2-59 months with community acquired very severe pneumonia in low resource settings.
Design Open label randomised controlled trial.
Setting Inpatient wards within tertiary care hospitals in Bangladesh, Ecuador, India, Mexico, Pakistan, Yemen, and Zambia.
Participants Children aged 2-59 months with WHO defined very severe pneumonia.
Intervention Chloramphenicol versus a combination of ampicillin plus gentamicin.
Main outcome measures Primary outcome measure was treatment failure at five days. Secondary outcomes were treatment failure defined similarly among all participants evaluated at 48 hours and at 10 and 21 days.
Results More children failed treatment with chloramphenicol at day 5 (16% v 11%; relative risk 1.43, 95% confidence interval 1.03 to 1.97) and also by days 10 and 21. Overall, 112 bacterial isolates were obtained from blood and lung aspirates in 110 children (11.5%), with the most common organisms being Staphylococcus aureus (n=47) and Streptococcus pneumoniae (n=22). In subgroup analysis, bacteraemia with any organism increased the risk of treatment failure at 21 days in the chloramphenicol group (2.09, 1.41 to 3.10) but not in the ampicillin plus gentamicin group (1.12, 0.59 to 2.13). Similarly, isolation of S pneumoniae increased the risk of treatment failure at day 21 (4.06, 2.73 to 6.03) and death (5.80, 2.62 to 12.85) in the chloramphenicol group but not in the ampicillin plus gentamicin group. No difference was found in treatment failure for children with S aureus bacteraemia in the two groups, but the power to detect a difference in this subgroup analysis was low. Independent predictors of treatment failure by multivariate analysis were hypoxaemia (oxygen saturation <90%), receiving chloramphenicol, being female, and poor immunisation status.
Conclusion Injectable ampicillin plus gentamicin is superior to injectable chloramphenicol for the treatment of community acquired very severe pneumonia in children aged 2-59 months in low resource settings.
Trial registration Current Controlled Trials ISRCTN39543942.
doi:10.1136/bmj.39421.435949.BE
PMCID: PMC2190277  PMID: 18182412
11.  Acceptability of Massage with Skin Barrier-enhancing Emollients in Young Neonates in Bangladesh 
Oil massage of newborns has been practised for generations in the Indian sub-continent; however, oils may vary from potentially beneficial, e.g. sunflower seed oil, to potentially toxic, e.g. mustard oil. The study was carried out to gain insights into oil-massage practices and acceptability of skin barrier-enhancing emollients in young, preterm Bangladeshi neonates. Preterm infants of <33 weeks gestational age were randomized to high-linoleate sunflower seed oil, Aquaphor Original Emollient Ointment™, or the comparison group (usual care). A survey was administered at admission to assess routine skin-care practices prior to admission and at discharge to assess acceptability of emollient therapy during hospitalization. Oil massage was given to 83 (21%) of 405 babies before hospital admission, 86% (71/83) of whom were delivered at home. Application of oil, most commonly mustard oil (88%, 73/83), was started within one hour of birth in 51 cases (61%) and was applied all over the body (89%, 74/83) one to six (mean 2.2) times before admission. Of infants who received emollient therapy in the hospital, 42% (n=32) of mothers reported that the emollient applied in the hospital was better than that available at home, and only 29% would use the same oil (i.e. mustard oil) in the future as used previously at home. No problems resulted from use of emollient in the hospital. Topical therapy with sunflower seed oil or Aquaphor was perceived by many families to be superior to mustard oil. If caregivers and health professionals can be motivated to use inexpensive, available emollients, such as sunflower seed oil that are beneficial, emollient therapy could have substantial public-health benefit.
PMCID: PMC2754003  PMID: 17985826
Bathing; Emollient; Oil massage; Prospective studies; Skin; Bangladesh

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