John Hussman

This paper has been reprinted and distributed for academic and informational purposes only. All rights reserved and actively enforced. Commercial use of any portion is prohibited. The methods and investment strategies presented in this research are purely expositional. It should not be assumed that the Market Climates derived from the limited criteria in this research will reflect the actual positions taken by the Hussman Funds in practice. Abstract Market efficiency implies a positive relationship between market risk and expected return. Using ex-ante conditioning variables implied by the definition of total return, the time series of U.S. stock market data is partitioned into a set of conditional distributions. These distributions suggest that market risk is not universally efficient, but displays varying degrees of efficiency in generating expected return. The conditional distributions also exhibit differences in the expected mix of positive and negative outlier returns, Sharpe r...

Abstract: The paper examines time series properties and efficiency of a securities market where disparately informed traders hold rational expectations and extract signals from the endogenous market price. Two equilibria are calculated, using a method of Sargent to handle the problem of infinite regress. When rational speculation is the sole source of potential trade, the market price reflects all private information, and zero trade occurs. When net supply is perturbed by unobserved noise, the market exhibits a broad range of characteristics cited in empirical literature, including excess volatility, mean reversion, dividend yield effects, trading volume and divergence of opinion. I am indebted to Thomas J. Sargent for helpful discussions. Are securities prices too volatile? This question is central to evaluating how efficiently resources are allocated in a competitive market. A large body of literature suggests that securities markets will generate prices which reflect all availabl...

Infection by the novel SARS-CoV-2 coronavirus produces a range of outcomes, with the majority of cases producing mild or asymptomatic effects, and a smaller subset progressing to critical or fatal COVID-19 disease featuring severe acute respiratory distress. Although the mechanisms driving severe disease progression remain unknown, it is possible that the abrupt clinical deterioration observed in patients with critical disease corresponds to a discrete underlying expansion of viral tropism, from infection of cells comprising respiratory linings and alveolar epithelia to direct infection and activation of inflammatory monocytes and macrophages. Dysregulated immune responses could then contribute to disease severity. This article discusses the potential role of monocyte/macrophage (Mo/Mϕ) infection by SARS-CoV-2 in mediating the immune response in severe COVID-19. Additional mechanisms of immune-enhanced disease, comprising maladaptive immune responses that may aggravate rather than a...

The basal ganglia are a collection of nuclei below the cortical surface that are involved in both motor and non-motor functions, including higher order cognition, social interactions, speech, and repetitive behaviors. Motor development milestones that are delayed in autism such as gross motor, fine motor and walking can aid in early diagnosis of autism. Neuropathology and neuroimaging findings in autism cases revealed volumetric changes and altered cell density in select basal ganglia nuclei. Interestingly, in autism, both the basal ganglia and the cerebellum are impacted both in their motor and non-motor domains and recently, found to be connected via the pons through a short disynaptic pathway. In typically developing individuals, the basal ganglia plays an important role in: eye movement, movement coordination, sensory modulation and processing, eye-hand coordination, action chaining, and inhibition control. Genetic models have proved to be useful toward understanding cellular and molecular changes at the synaptic level in the basal ganglia that may in part contribute to these autism-related behaviors. In autism, basal ganglia functions in motor skill acquisition and development are altered, thus disrupting the normal flow of feedback to the cortex. Taken together, there is an abundance of emerging evidence that the basal ganglia likely plays critical roles in maintaining an inhibitory balance between cortical and subcortical structures, critical for normal motor actions and cognitive functions. In autism, this inhibitory balance is disturbed thus impacting key pathways that affect normal cortical network activity. Autism Res 2017, 10: 1751-1775. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain.

Autism Spectrum Disorder (ASD) is a behaviorally defined neurodevelopmental condition. Symptoms of ASD cover the spectrum from mild qualitative differences in social interaction to severe communication and social and behavioral challenges that require lifelong support. Attempts at understanding the pathophysiology of ASD have been hampered by a multifactorial etiology that stretches the limits of current behavioral and cell based models. Recent progress has implicated numerous autism-risk genes but efforts to gain a better understanding of the underlying biological mechanisms have seen slow progress. This is in part due to lack of appropriate models for complete molecular and pharmacological studies. The advent of induced pluripotent stem cells (iPSC) has reinvigorated efforts to establish more complete model systems that more reliably identify molecular pathways and predict effective drug targets and candidates in ASD. iPSCs are particularly appealing because they can be derived from human patients and controls for research purposes and provide a technology for the development of a personalized treatment regimen for ASD patients. The pluripotency of iPSCs allow them to be reprogrammed into a number of CNS cell types and phenotypically screened across many patients. This quality is already being exploited in protocols to generate 2-dimensional (2-D) and three-dimensional (3-D) models of neurons and developing brain structures. iPSC models make powerful platforms that can be interrogated using electrophysiology, gene expression studies, and other cell-based quantitative assays. iPSC technology has limitations but when combined with other model systems has great potential for helping define the underlying pathophysiology of ASD. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive an...

Background: Autism has a strong genetic component but studies over the past decade have demonstrated that the underlying genetics are complex. Previous studies suggest an important role for copy number variants (CNVs) in autism risk and indicate a strong association of de novo copy number mutations with autism. The GABRA4 gene is implicated in autism risk through both cytogenetic alterations in autism patients in the GABR chromosome 4p region and through association with SNPs in the GABRA4 gene in autistic families. These data point to GABRA4 and potentially other GABR genes in this region as autism candidate genes. Objectives: To examine the GABRA4 gene for possible disease associated CNVs within or near the GABRA4 gene. Methods: Using DNA collected from 428 autism family probands and 190 controls, we performed quantitative real-time PCR (qPCR) with unique probes located within or near the GABRA4 gene spanning an area of almost 100 kb to identify the presence of duplications and de...

Background: Autism and epilepsy are common complex disorders which independently result in significant behavioral and developmental problems. Their co-occurrence, which often results in a more severe phenotype and extremely poor prognosis, is conservatively estimated at 25% to 30%.The biologic mechanisms that account for this co-occurrence have eluded discovery. Several conceptual models have proposed a common brain pathology in which autism and epilepsy are independent consequences of the same underlying disorder. Given the overlap in these two disorders we proposed that epilepsy risk genes could be etiologically relevant to autism. Objectives: To test the hypothesis that epilepsy related candidate genes may confer risk to autism. Methods: Using existing genome wide association study (GWAS) data, we examined 20 candidate genes, selected on the basis of previous reports of association or biological relevance to epilepsy or epilepsy and co-occurring autism. The discovery dataset cons...

Background Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. Methods GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) ...

... Against the Beta-Expected Return Relationship John P. Hussman University of Michigan ... relation between risk, as measured by β, and expected return. This paper demonstrates that using monthly returns data, the cross-sectional regression approach will accept the ...

The primary inhibitory and excitatory amino acid neurotransmitters are gamma-aminobutyric acid (GABA) and glutamate, respectively. Despite their pervasiveness in brain function and sensory processes, the amino acid neurotransmitters have received limited attention in the study ...

Unlike other complex diseases, the study of autism has been almost exclusively limited to Caucasian families. This study represents a first effort to examine clinical and phenotypic findings in individuals with autism from African American families. Drawing from an ongoing genetic study of autism we compared African American (N = 46, mean age = 118 months) and Caucasian (N = 298, mean age = 105 months) groups on autism symptoms and developmental language symptoms. The African American group showed greater delays in language but did not differ from the Caucasian group on core autism symptoms. These findings, while suggestive of a more severe phenotype, may reflect an ascertainment bias. Nonetheless, we believe that more studies of racial-ethnic groups should be conducted with several goals in mind including strengthening recruiting strategies to include more ethnic-racial groups and more thoughtful evaluation of phenotypic traits. Such considerations will aid greatly in the search for genetic variants in autism.