The Autism studies/research thread

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Abstract
Methods
The study was conducted using a repeated measures research design. Retrospective chart review data were collected from 62 individuals with autism, age (M=8.65, SD=4.53), all of whom were level two autistic and required moderate support in communication, socialization, and daily life. These individuals received ABA treatment over five months. The study measured cumulative target behaviors using a repeated measures design, which allowed for the identification of statistically significant differences across 12 time points. This robust methodology ensures the validity and reliability of the study's findings.

Results
Mixed repeated measures analysis of variance (ANOVA) indicated statistical significance (sphericity assumed), F(11,495) = 55.432, p < 0.001 (time). Multiple comparisons using bootstrapped paired t-tests showed p < 0.05 on time points 1-8 and non-significance (p > 0.05) on time points 9-12. There was a significant interaction effect (sphericity assumed) with time x (age category), F(44,495) = 2.338, p < 0.001. Interaction contrasts indicated statistically significant differences over time, mainly within the one-year to four-year-old, five to eight-year-old, and most in the nine to 12-year-old age groups. There was some significance within the 13- to 16-year-old age group and no significance within the 17- to 26-year-old age group.

Conclusions
Over five months, individuals with autism who underwent ABA treatments demonstrated a statistically significant enhancement in general target behaviors. This finding is crucial as it underscores the effectiveness of ABA treatments in a naturalistic environment. Moreover, the study's discovery of a significant interaction between time and age in these behaviors provides valuable insights into the impact of age on treatment outcomes. Extensive large-N studies of general ABA broad effectiveness and repeated measures designs are lacking and can lead to further research to improve quality and outcomes. These findings contribute to the body of empirical evidence and emphasize the importance of replicative efficacy studies in ensuring the reliability of research findings.

The incidence of autism spectrum disorder was higher among children exposed to topiramate in the second half of pregnancy than in the general population, but not relative to other children born to women with epilepsy, a study of 4 million pregnant women and their children showed.

At age 8, 1.89% of children who had never been prenatally exposed to an antiseizure medication were diagnosed with autism spectrum disorder, reported Sonia Hernández-Díaz, MD, DrPH, of the Harvard T.H. Chan School of Public Health in Boston, and co-authors.

For children born to mothers with epilepsy, however, the crude incidence of autism at age 8 was 4.21% with no prenatal exposure to an antiseizure medication, 6.15% with exposure to topiramate, 10.51% with exposure to valproate, and 4.08% with exposure to lamotrigine, the researchers wrote in the New England Journal of Medicine

After adjusting for indication and other variables, only valproate was associated with additional autism risk, Hernández-Díaz and colleagues said. Compared with no exposure to antiseizure medication, weighted average hazard ratios (HRs) were 0.96 (95% CI 0.56-1.65) for topiramate exposure, 2.67 (95% CI 1.69-4.20) for valproate, and 1.00 (95% CI 0.69-1.46) for lamotrigine.

"Overall, results suggest no substantially increased risk of autism spectrum disorder after prenatal exposure to either topiramate or lamotrigine (the negative control group) and a dose-dependent increased risk of autism spectrum disorder associated with prenatal valproate exposure (the positive control group)," the researchers wrote.

Valproate is a known teratogen; its label carries a boxed warningopens in a new tab or window that prenatal exposure may lead to cognitive deficits or physical birth defects. Most studies of other antiseizure medications have not shown increased risksopens in a new tab or window of neurodevelopmental disorders.

A recent Nordic studyopens in a new tab or window, however, reported an increased incidence of autism after prenatal exposure to topiramate, triggering a safety reviewopens in a new tab or window of the drug by U.K. health authorities. Last year, the European Medicines Agency's safety committee recommended new measures to avoid topiramate exposureopens in a new tab or window in pregnancy.

In the U.S., the FDA has warned of an increased risk of oral cleftsopens in a new tab or window in infants born to women treated with topiramate.

However, a full understanding of potential neuropsychological risks of topiramate and many other antiseizure medications requires further basic and clinical investigations," Meador pointed out. "Fetal exposure to topiramate has been associated with an increased incidence of congenital malformationsopens in a new tab or window (3.9 to 4.1% among exposed infants vs 3% in the general population) and of small size for gestational age."

Teratogenic risks for many other antiseizure medications remain unknown "and the pace of advancement is painfully slow," he continued. The need for more research is underscored by the substantial costs associated with fetal medication exposures, he added: "The lifetime financial costs of just cognitive deficits related to fetal exposure to valproate in the United States in 2006 alone were estimated to be $626 million."

Hernández-Díaz and co-authors studied pregnancy cohorts nested in Medicaid data from 2000 through 2018 and in MarketScan commercial health insurance data from 2003 through 2020. Records included 4.2 million children eligible at birth; more than 400,000 children were followed for at least 8 years. The median follow-up was 2 years.

The study had several limitations, the researchers said. Though the cohort remained large, many children were lost to follow-up by age 8. Filled prescriptions were used as a proxy for actual medication use. Due to the relatively small number of cases of autism, confidence intervals for hazard ratios were wide.

Chemicals found in common household items could be damaging our brains, scientists have warned, with potential links to a range of neurological conditions including multiple sclerosis and autism.

On a daily basis, we are exposed to hundreds of different chemicals, the health effects of which are mostly unknown. To explore these effects, a team of researchers from Case Western Reserve University's School of Medicine analyzed over 1,800 household chemicals found in common household cleaners, beauty products and flame retardants.

Most previous studies on the effects of these chemicals on brain health have focused on neuronal cells in the brain, which basically act like the brain's wiring. But much less is known about the effects of these chemicals on the brain's supporting cells. Thus, the team decided to focus it efforts on the cells that wrap around our neurons and improve their ability to transmit information. Called oligodendrocytes, they form the brain's white matte and function like the colorful cable insulation we see around copper wires.

Using oligodendrocytes isolated from mice and cultured human cells, the team found that 292 of the chemicals tested were deadly to these insulating brain cells, with a further 47 inhibiting oligodendrocyte generation. Their results were published in the journal Nature Neuroscience.

Autism has proven to be one of the most difficult-to-treat indications, but troublesome symptoms may someday find new relief. Last week, Roche Holdings (NASDAQOTH: RHHBY) announced it had received breakthrough therapy status from the Food and Drug Administration for balovaptan, a potential therapy for autism spectrum disorder.

If future trials confirm balovaptan's promise, it could improve social interaction and communication in people with autism.

The drug that may help someday
In midstage studies, Roche's balovaptan has shown promise that it may help improve social behavior in autistic adults.

Balovaptan is a V1a vasopressin receptor antagonist that blocks or dampens the biological response to vasopressin, a hormone. Historically, vasopressin is known for its role in regulating the volume of water in the body and influencing blood pressure. However, researchers increasingly believe that vasopressin imbalances may contribute to autism, particularly in boys, in whom high levels of vasopressin have been connected to anxiety and aggression.

At the International Meeting for Autism Research in San Francisco last year, trial data was presented showing that balovaptan taken once daily for 12 weeks significantly improved socialization and communication abilities, as measured by the Vineland Adaptive Behavior Scales. Specifically, study participants who took intermediate and high doses of balovaptan saw their scores on this scale improve by roughly four to five points, results that researchers said were "above the threshold for what we consider a minimum clinically important difference."

What’s Next
The FDA designation of breakthrough status can accelerate balovaptan's development, but there's still a lot of work to be done.

Before the FDA will consider approving balovaptan, Roche needs to complete its ongoing study in children between the ages of 5 to 17 years. If results from that study are also positive, then Roche can sit down with regulators to discuss whether any additional trials will be necessary before filing for approval. According to ClinicalTrials.gov, we have some waiting to do; the estimated completion date for the children's study isn't until April 2019. Based on that timeline, we're still a couple of years away from knowing that balovaptan is a safe and effective treatment for symptoms associated with autism.

Key Points
Question What are the sex-specific etiological origins of autism spectrum disorder?

Findings In this cohort study including 1 047 649 Swedish children, 12 226 (1.17%) received a diagnosis of autism spectrum disorder; heritability was estimated at 87.0% for males and 75.7% for females, a statistically significant difference.

Meaning These findings suggest that variation in the occurrence of autism spectrum disorder in the population differs between males and females, indicating that some of the underlying causes and prevalence of the condition may differ between the 2 sexes.

Abstract
Importance Autism spectrum disorder (ASD) is a neurodevelopmental disorder more prevalent in males than in females. The cause of ASD is largely genetic, but the association of genetics with the skewed sex ratio is not yet understood. To our knowledge, no large population-based study has provided estimates of heritability by sex.

Objective To estimate the sex-specific heritability of ASD.

Design, Setting, and Participants. This was a population-based, retrospective analysis using national health registers of nontwin siblings and cousins from Sweden born between January 1, 1985, and December 31, 1998, with follow-up to 19 years of age. Data analysis occurred from August 2022 to November 2023.

Main Outcomes and Measures Models were fitted to estimate the relative variance in risk for ASD occurrence owing to sex-specific additive genetics, shared environmental effects, and a common residual term. The residual term conceptually captured other factors that promote individual behavioral variation (eg, maternal effects, de novo variants, rare genetic variants not additively inherited, or gene-environment interactions). Estimates were adjusted for differences in prevalence due to birth year and maternal and paternal age by sex.

Results The sample included 1 047 649 individuals in 456 832 families (538 283 males [51.38%]; 509 366 females [48.62%]). Within the entire sample, 12 226 (1.17%) received a diagnosis of ASD, comprising 8128 (1.51%) males and 4098 (0.80%) females. ASD heritability was estimated at 87.0% (95% CI, 81.4%-92.6%) for males and 75.7% (95% CI, 68.4%-83.1%) for females with a difference in heritability estimated at 11.3% (95% CI, 1.0%-21.6%). There was no support for shared environmental contributions.

Conclusions and Relevance These findings suggest that the degree of phenotypic variation attributable to genetic differences (heritability) differs between males and females, indicating that some of the underlying causes of the condition may differ between the 2 sexes. The skewed sex ratio in ASD may be partly explained by differences in genetic variance between the sexes.