Precise characterization of cognitive outcomes and factors that contribute to cognitive variabili... more Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.
The 2014 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting focused on the dual themes... more The 2014 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting focused on the dual themes of the risks associated with low to moderate alcohol exposure during pregnancy and knowledge translation practices to enhance the impact of scientific research. The meeting theme was titled "Low drinking versus no drinking: Matching science with policy and public perception." Despite decades of basic science and clinical evidence that has documented the risks associated with prenatal alcohol exposure, there still exists confusion and uncertainty on the part of health professionals and the public regarding the question of whether or not there is a "safe" level of alcohol consumption during pregnancy. The first keynote presentation reviewed the data obtained from large-scale epidemiological studies that have attempted to address the question of relative risk associated with low to moderate alcohol exposure during pregnancy. This presentation was followed by an expert panel discussion of the state of scientific evidence obtained from clinical and basic science investigations concerning this question, and strategies for moving research evidence into policy and practice. The second keynote presentation presented a framework for knowledge translation and mobilization to move research discoveries toward implementation. The conference also featured updates by government agencies, FASt data talks that highlighted new and innovative findings in FASD research, and award presentations, including a lifetime achievement award presented to Dr. Kenneth Warren to acknowledge his longstanding support for FASD research. A highlight of the meeting was the presentation of the 2014 Henry Rosett award to Dr. Philip May in recognition of his substantial contributions to epidemiological studies on FASD.
Brain functional connectivity has been studied by analyzing time series correlations in regional ... more Brain functional connectivity has been studied by analyzing time series correlations in regional brain activities based on resting-state fMRI data. Brain functional connectivity can be depicted as a network or graph defined as a set of nodes linked by edges. Nodes represent brain regions and an edge measures the strength of functional correlation between two regions. Most of existing work focuses on estimation of such a network. A key but inadequately addressed question is how to test for possible differences of the networks between two subject groups, say between healthy controls and patients. Here we illustrate and compare the performance of several state-of-the-art statistical tests drawn from the neuroimaging, genetics, ecology and high-dimensional data literatures. Both real and simulated data were used to evaluate the methods. We found that Network Based Statistic (NBS) performed well in many but not all situations, and its performance critically depends on the choice of its t...
Resting-state functional magnetic resonance imaging allows one to study brain functional connecti... more Resting-state functional magnetic resonance imaging allows one to study brain functional connectivity, partly motivated by evidence that patients with complex disorders, such as Alzheimer's disease, may have altered functional brain connectivity patterns as compared with healthy subjects. A functional connectivity network describes statistical associations of the neural activities among distinct and distant brain regions. Recently, there is a major interest in group-level functional network analysis; however, there is a relative lack of studies on statistical inference, such as significance testing for group comparisons. In particular, it is still debatable which statistic should be used to measure pairwise associations as the connectivity weights. Many functional connectivity studies have used either (full or marginal) correlations or partial correlations for pairwise associations. This article investigates the performance of using either correlations or partial correlations for testing group differences in brain connectivity, and how sparsity levels and topological structures of the connectivity would influence statistical power to detect group differences. Our results suggest that, in general, testing group differences in networks deviates from estimating networks. For example, high regularization in both covariance matrices and precision matrices may lead to higher statistical power; in particular, optimally selected regularization (e.g., by cross-validation or even at the true sparsity level) on the precision matrices with small estimation errors may have low power. Most importantly, and perhaps surprisingly, using either correlations or partial correlations may give very different testing results, depending on which of the covariance matrices and the precision matrices are sparse. Specifically, if the precision matrices are sparse, presumably and arguably a reasonable assumption, then using correlations often yields much higher powered and more stable testing results than using partial correlations; the conclusion is reversed if the covariance matrices, not the precision matrices, are sparse. These results may have useful implications to future studies on testing functional connectivity differences.
Cocaine dependence is a particularly severe problem in the United States, resulting in broad econ... more Cocaine dependence is a particularly severe problem in the United States, resulting in broad economic and personal costs. Significant evidence of generalized cognitive deficits associated with cocaine dependence has been reported. Two studies evaluated whether context processing, the processes involved in representing and maintaining information regarding the context of one's environment, might be seen as a process-specific deficit that may explain some aspects of the broader cognitive deficits associated with cocaine dependence. Study 1 used the expectancy variant of the AX task to assess this ability; Study 2 employed the Dot Pattern Expectancy task. Significant between-groups differences were found in each study for d'-context, a comparison of AX hits and BX misses; these results indicated significant between-groups differences in context-processing ability. In Study 1, significant between-groups a priori contrasts of AY versus BX trials indicated the likelihood of a specific deficit in context processing in the cocaine group; however, this contrast was not significant in Study 2. Overall, the results of these studies support the theory of impaired context-processing ability associated with cocaine misuse. However, these results do not allow for the interpretation of a process-specific deficit in context-processing ability. Future research targeted at investigating aspects of this context-processing impairment associated with cocaine misuse can shed light on the specificity of this deficit.
Schizophrenia is a heterogeneous neurodevelopmental disorder. Patients with high levels of negati... more Schizophrenia is a heterogeneous neurodevelopmental disorder. Patients with high levels of negative symptoms have been identified as a specific subtype, but little is known about how the neurodevelopmental course may differ in this group. This study aimed to characterize developmental trajectories of premorbid social withdrawal and cognitive decline between patients with high versus low levels of negative symptoms in youth with schizophrenia-spectrum disorders. A standardized timeline was used to delineate the emergence of psychosis, social withdrawal, and cognitive decline in 52 subjects aged 8 to 19 with schizophrenia (n=36), schizophreniform (n=6), or schizoaffective disorder (n=10). The sample was divided into subgroups of high- (n=26) versus low- (n=26) negative symptoms, and developmental trajectories of premorbid symptoms were compared between groups. Mean ages for emergence of social withdrawal, cognitive decline, and psychosis were 11.1 years (SD=2.5), 11.9 (SD=4.4) and 13.2 years (SD=1.2), respectively. In the high-negative symptom group, the premorbid developmental trajectory for social withdrawal was more protracted. This group also had more severe cognitive decline at the onset of psychosis, but the premorbid trajectories for cognitive decline did not differ significantly between groups. This work documents a more severe and protracted trajectory of premorbid social withdrawal in patients with high levels of negative symptoms in comparison to those with low-negative symptoms. The findings reported here are supportive of the hypothesis that patients with illness characterized by high levels of negative symptoms may represent a subgroup with distinct neurodevelopmental abnormalities.
Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the... more Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the vast majority of available evidence comes from school-age children and adolescents. Very little is known about EF during the critical developmental period prior to 6 years of age in FASD. We evaluated EF in 39 children with FASD (3.0 – 5.5 years) and a comparison group of 50 age-matched, non-exposed controls. Measures included the EF Scale for Early Childhood and a Delay of Gratification task. Compared to age-matched controls, preschool children with FASD had impairments on the EF Scale and showed more impulsivity on the Delay of Gratification task. To confirm the EF Scale finding, FASD group performance was compared to a separate normative dataset (N=1,400). Those with FASD performed below normal (M= −0.57, SD=0.92). Within the FASD group, IQ was correlated with the EF Scale (partial r=.60, p=.001) and Delay of Gratification (partial r=.58, p=.005). EF Scale performance did not differ significantly across levels of FASD severity [fetal alcohol syndrome (FAS), partial FAS, or alcohol-related neurobehavioral disorder (ARND)]. However, compared to normative data, those with FAS had the largest deficits (M= −0.91 SD, SE=0.23), followed by partial FAS (M= −0.66 SD, SE=0.26), then ARND (M= −0.36 SD, SE=0.20). These novel data show that EF deficits manifest well before the age of 6 years in children with FASD, that they occur across the spectrum, and that EF may be most impaired in children with more severe forms of FASD and/or lower IQs.
The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, ... more The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.
Precise characterization of cognitive outcomes and factors that contribute to cognitive variabili... more Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.
The 2014 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting focused on the dual themes... more The 2014 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting focused on the dual themes of the risks associated with low to moderate alcohol exposure during pregnancy and knowledge translation practices to enhance the impact of scientific research. The meeting theme was titled "Low drinking versus no drinking: Matching science with policy and public perception." Despite decades of basic science and clinical evidence that has documented the risks associated with prenatal alcohol exposure, there still exists confusion and uncertainty on the part of health professionals and the public regarding the question of whether or not there is a "safe" level of alcohol consumption during pregnancy. The first keynote presentation reviewed the data obtained from large-scale epidemiological studies that have attempted to address the question of relative risk associated with low to moderate alcohol exposure during pregnancy. This presentation was followed by an expert panel discussion of the state of scientific evidence obtained from clinical and basic science investigations concerning this question, and strategies for moving research evidence into policy and practice. The second keynote presentation presented a framework for knowledge translation and mobilization to move research discoveries toward implementation. The conference also featured updates by government agencies, FASt data talks that highlighted new and innovative findings in FASD research, and award presentations, including a lifetime achievement award presented to Dr. Kenneth Warren to acknowledge his longstanding support for FASD research. A highlight of the meeting was the presentation of the 2014 Henry Rosett award to Dr. Philip May in recognition of his substantial contributions to epidemiological studies on FASD.
Brain functional connectivity has been studied by analyzing time series correlations in regional ... more Brain functional connectivity has been studied by analyzing time series correlations in regional brain activities based on resting-state fMRI data. Brain functional connectivity can be depicted as a network or graph defined as a set of nodes linked by edges. Nodes represent brain regions and an edge measures the strength of functional correlation between two regions. Most of existing work focuses on estimation of such a network. A key but inadequately addressed question is how to test for possible differences of the networks between two subject groups, say between healthy controls and patients. Here we illustrate and compare the performance of several state-of-the-art statistical tests drawn from the neuroimaging, genetics, ecology and high-dimensional data literatures. Both real and simulated data were used to evaluate the methods. We found that Network Based Statistic (NBS) performed well in many but not all situations, and its performance critically depends on the choice of its t...
Resting-state functional magnetic resonance imaging allows one to study brain functional connecti... more Resting-state functional magnetic resonance imaging allows one to study brain functional connectivity, partly motivated by evidence that patients with complex disorders, such as Alzheimer's disease, may have altered functional brain connectivity patterns as compared with healthy subjects. A functional connectivity network describes statistical associations of the neural activities among distinct and distant brain regions. Recently, there is a major interest in group-level functional network analysis; however, there is a relative lack of studies on statistical inference, such as significance testing for group comparisons. In particular, it is still debatable which statistic should be used to measure pairwise associations as the connectivity weights. Many functional connectivity studies have used either (full or marginal) correlations or partial correlations for pairwise associations. This article investigates the performance of using either correlations or partial correlations for testing group differences in brain connectivity, and how sparsity levels and topological structures of the connectivity would influence statistical power to detect group differences. Our results suggest that, in general, testing group differences in networks deviates from estimating networks. For example, high regularization in both covariance matrices and precision matrices may lead to higher statistical power; in particular, optimally selected regularization (e.g., by cross-validation or even at the true sparsity level) on the precision matrices with small estimation errors may have low power. Most importantly, and perhaps surprisingly, using either correlations or partial correlations may give very different testing results, depending on which of the covariance matrices and the precision matrices are sparse. Specifically, if the precision matrices are sparse, presumably and arguably a reasonable assumption, then using correlations often yields much higher powered and more stable testing results than using partial correlations; the conclusion is reversed if the covariance matrices, not the precision matrices, are sparse. These results may have useful implications to future studies on testing functional connectivity differences.
Cocaine dependence is a particularly severe problem in the United States, resulting in broad econ... more Cocaine dependence is a particularly severe problem in the United States, resulting in broad economic and personal costs. Significant evidence of generalized cognitive deficits associated with cocaine dependence has been reported. Two studies evaluated whether context processing, the processes involved in representing and maintaining information regarding the context of one's environment, might be seen as a process-specific deficit that may explain some aspects of the broader cognitive deficits associated with cocaine dependence. Study 1 used the expectancy variant of the AX task to assess this ability; Study 2 employed the Dot Pattern Expectancy task. Significant between-groups differences were found in each study for d'-context, a comparison of AX hits and BX misses; these results indicated significant between-groups differences in context-processing ability. In Study 1, significant between-groups a priori contrasts of AY versus BX trials indicated the likelihood of a specific deficit in context processing in the cocaine group; however, this contrast was not significant in Study 2. Overall, the results of these studies support the theory of impaired context-processing ability associated with cocaine misuse. However, these results do not allow for the interpretation of a process-specific deficit in context-processing ability. Future research targeted at investigating aspects of this context-processing impairment associated with cocaine misuse can shed light on the specificity of this deficit.
Schizophrenia is a heterogeneous neurodevelopmental disorder. Patients with high levels of negati... more Schizophrenia is a heterogeneous neurodevelopmental disorder. Patients with high levels of negative symptoms have been identified as a specific subtype, but little is known about how the neurodevelopmental course may differ in this group. This study aimed to characterize developmental trajectories of premorbid social withdrawal and cognitive decline between patients with high versus low levels of negative symptoms in youth with schizophrenia-spectrum disorders. A standardized timeline was used to delineate the emergence of psychosis, social withdrawal, and cognitive decline in 52 subjects aged 8 to 19 with schizophrenia (n=36), schizophreniform (n=6), or schizoaffective disorder (n=10). The sample was divided into subgroups of high- (n=26) versus low- (n=26) negative symptoms, and developmental trajectories of premorbid symptoms were compared between groups. Mean ages for emergence of social withdrawal, cognitive decline, and psychosis were 11.1 years (SD=2.5), 11.9 (SD=4.4) and 13.2 years (SD=1.2), respectively. In the high-negative symptom group, the premorbid developmental trajectory for social withdrawal was more protracted. This group also had more severe cognitive decline at the onset of psychosis, but the premorbid trajectories for cognitive decline did not differ significantly between groups. This work documents a more severe and protracted trajectory of premorbid social withdrawal in patients with high levels of negative symptoms in comparison to those with low-negative symptoms. The findings reported here are supportive of the hypothesis that patients with illness characterized by high levels of negative symptoms may represent a subgroup with distinct neurodevelopmental abnormalities.
Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the... more Executive function (EF) deficit is a hallmark of Fetal Alcohol Spectrum Disorders (FASD), but the vast majority of available evidence comes from school-age children and adolescents. Very little is known about EF during the critical developmental period prior to 6 years of age in FASD. We evaluated EF in 39 children with FASD (3.0 – 5.5 years) and a comparison group of 50 age-matched, non-exposed controls. Measures included the EF Scale for Early Childhood and a Delay of Gratification task. Compared to age-matched controls, preschool children with FASD had impairments on the EF Scale and showed more impulsivity on the Delay of Gratification task. To confirm the EF Scale finding, FASD group performance was compared to a separate normative dataset (N=1,400). Those with FASD performed below normal (M= −0.57, SD=0.92). Within the FASD group, IQ was correlated with the EF Scale (partial r=.60, p=.001) and Delay of Gratification (partial r=.58, p=.005). EF Scale performance did not differ significantly across levels of FASD severity [fetal alcohol syndrome (FAS), partial FAS, or alcohol-related neurobehavioral disorder (ARND)]. However, compared to normative data, those with FAS had the largest deficits (M= −0.91 SD, SE=0.23), followed by partial FAS (M= −0.66 SD, SE=0.26), then ARND (M= −0.36 SD, SE=0.20). These novel data show that EF deficits manifest well before the age of 6 years in children with FASD, that they occur across the spectrum, and that EF may be most impaired in children with more severe forms of FASD and/or lower IQs.
The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, ... more The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.
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Papers by Jeffrey Wozniak