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1.  Weighted Hurdle Regression Method for Joint Modeling of Cardiovascular Events Likelihood and Rate in the U.S. Dialysis Population 
Statistics in medicine  2014;33(25):4387-4401.
SUMMARY
We propose a new weighted hurdle regression method for modeling count data, with particular interest in modeling cardiovascular events in patients on dialysis. Cardiovascular disease remains one of the leading causes of hospitalization and death in this population. Our aim is to jointly model the relationship/association between covariates and (a) the probability of cardiovascular events, a binary process and (b) the rate of events once the realization is positive - when the ‘hurdle’ is crossed - using a zero-truncated Poisson distribution. When the observation period or follow-up time, from the start of dialysis, varies among individuals the estimated probability of positive cardiovascular events during the study period will be biased. Furthermore, when the model contains covariates, then the estimated relationship between the covariates and the probability of cardiovascular events will also be biased. These challenges are addressed with the proposed weighted hurdle regression method. Estimation for the weighted hurdle regression model is a weighted likelihood approach, where standard maximum likelihood estimation can be utilized. The method is illustrated with data from the United States Renal Data System. Simulation studies show the ability of proposed method to successfully adjust for differential follow-up times and incorporate the effects of covariates in the weighting.
doi:10.1002/sim.6232
PMCID: PMC4184989  PMID: 24930810
cardiovascular outcomes; dialysis; end stage renal disease; hurdle model; infection; Poisson regression; United States Renal Data System
2.  Design considerations for case series models with exposure onset measurement error 
Statistics in medicine  2012;32(5):772-786.
Summary
The case series model allows for estimation of the relative incidence of events, such as cardiovascular events, within a pre-specified time window after an exposure, such as an infection. The method requires only cases (individuals with events) and controls for all fixed/time-invariant confounders. The measurement error case series model extends the original case series model to handle imperfect data, where the timing of an infection (exposure) is not known precisely. In this work, we propose a method for power/sample size determination for the measurement error case series model. Extensive simulation studies are used to assess the accuracy of the proposed sample size formulas. We also examine the magnitude of the relative loss of power due to exposure onset measurement error, compared to the ideal situation where the time of exposure is measured precisely. To facilitate the design of case series studies, we provide publicly available web-based tools for determining power/sample size for both the measurement error case series model as well as the standard case series model.
doi:10.1002/sim.5552
PMCID: PMC4075338  PMID: 22911898
case series models; exposure timing measurement error; longitudinal observational database; non-homogeneous Poisson process; sample size
3.  Measurement Error Case Series Models with Application to Infection-Cardiovascular Risk in OlderPatients on Dialysis 
Infection and cardiovascular disease are leading causes of hospitalization and death in older patients on dialysis. Our recent work found an increase in the relative incidence of cardiovascular outcomes during the ~ 30 days after infection-related hospitalizations using the case series model, which adjusts for measured and unmeasured baseline confounders. However, a major challenge in modeling/assessing the infection-cardiovascular risk hypothesis is that the exact time of infection, or more generally “exposure,” onsets cannot be ascertained based on hospitalization data. Only imprecise markers of the timing of infection onsets are available. Although there is a large literature on measurement error in the predictors in regression modeling, to date there is no work on measurement error on the timing of a time-varying exposure to our knowledge. Thus, we propose a new method, the measurement error case series (MECS) models, to account for measurement error in time-varying exposure onsets. We characterized the general nature of bias resulting from estimation that ignores measurement error and proposed a bias-corrected estimation for the MECS models. We examined in detail the accuracy of the proposed method to estimate the relative incidence. Hospitalization data from United States Renal Data System, which captures nearly all (> 99%) patients with end-stage renal disease in the U.S. over time, is used to illustrate the proposed method. The results suggest that the estimate of the cardiovascular incidence following the 30 days after infections, a period where acute effects of infection on vascular endothelium may be most pronounced, is substantially attenuated in the presence of infection onset measurement error.
doi:10.1080/01621459.2012.695648
PMCID: PMC3643015  PMID: 23650442
Cardiovascular outcomes; Case series models; End stage renal disease; Infection; Measurement error; Non-homogeneous Poisson process; Time-varying exposure onset; United States Renal Data System
4.  Memantine for Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): A Randomized, Double-Blind, Placebo-Controlled Trial 
Objective
Memantine, an NMDA receptor uncompetitive antagonist, is currently approved by the Food and Drug Administration for the treatment of moderate to severe Alzheimer’s disease. Anecdotal reports have suggested that memantine may improve neurological and cognitive symptoms of individuals with the neurodegenerative disease, fragile X-associated tremor tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial.
Method
A randomized, double-blind, placebo-controlled, one-year trial in individuals with FXTAS ages 34–80 years. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity.
Results
Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants on memantine and 36 on placebo completed the one-year endpoint assessment (n=70). Intention-to-treat analysis showed that there was no improvement with respect to intention tremor severity (memantine vs. placebo: 1.05 ± 0.73 vs. 1.89 ± 2.19, p=0.047) and BDS score (16.12 ± 5.43 vs. 15.72 ± 3.93, p=0.727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), late FXTAS (stage > 3) and different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events (AEs) were observed in the placebo group, while more frequent moderate AEs occurred in the memantine group (p=0.007).
Conclusion
This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit with respect to the selected outcome measures compared to placebo.
doi:10.4088/JCP.13m08546
PMCID: PMC4296896  PMID: 24345444
5.  Functional Linear Models for Zero-Inflated Count Data with Application to Modeling Hospitalizations in Patients on Dialysis 
Statistics in medicine  2014;33(27):4825-4840.
Summary
We propose functional linear models for zero-inflated count data with a focus on the functional hurdle and functional zero-inflated Poisson (ZIP) models. While the hurdle model assumes the counts come from a mixture of a degenerate distribution at zero and a zero-truncated Poisson distribution, the ZIP model considers a mixture of a degenerate distribution at zero and a standard Poisson distribution. We extend the generalized functional linear model framework with a functional predictor and multiple cross-sectional predictors to model counts generated by a mixture distribution. We propose an estimation procedure for functional hurdle and ZIP models, called penalized reconstruction (PR), geared towards error-prone and sparsely observed longitudinal functional predictors. The approach relies on dimension reduction and pooling of information across subjects involving basis expansions and penalized maximum likelihood techniques. The developed functional hurdle model is applied to modeling hospitalizations within the first two years from initiation of dialysis, with a high percentage of zeros, in the Comprehensive Dialysis Study participants. Hospitalization counts are modeled as a function of sparse longitudinal measurements of serum albumin concentrations, patient demographics and comorbidities. Simulation studies are used to study finite sample properties of the proposed method and include comparisons with an adaptation of standard principal components regression (PCR).
doi:10.1002/sim.6241
PMCID: PMC4221481  PMID: 24942314
functional data analysis; end stage renal disease; hurdle model; sparse longitudinal design; United States Renal Data System; zero-inflated Poisson model
6.  Naive Hypothesis Testing for Case Series Analysis with Time-Varying Exposure Onset Measurement Error: Inference for Infection-Cardiovascular Risk in Patients on Dialysis 
Biometrics  2013;69(2):520-529.
Summary
The case series method is useful in studying the relationship between time-varying exposures, such as infections, and acute events observed during the observation periods of individuals. It provides estimates of the relative incidences of events in risk periods (e.g., 30-day period after infections) relative to the baseline periods. When the times of exposure onsets are not known precisely, application of the case series model ignoring exposure onset measurement error leads to biased estimates. Bias-correction is necessary in order to understand the true directions and effect sizes associated with exposure risk periods, although uncorrected estimators have smaller variance. Thus, inference via hypothesis testing based on uncorrected test statistics, if valid, is potentially more powerful. Furthermore, the tests can be implemented in standard software and do not require additional auxiliary data. In this work, we examine the validity and power of naive hypothesis testing, based on applying the case series analysis to the imprecise data without correcting for the error. Based on simulation studies and theoretical calculations, we determine the validity and relative power of common hypothesis tests of interest in case series analysis. In particular, we illustrate that the tests for the global null hypothesis, the overall null hypotheses associated with all risk periods or all age effects are valid. However, tests of individual risk period parameters are not generally valid. Practical guidelines are provided and illustrated with data from patients on dialysis.
doi:10.1111/biom.12033
PMCID: PMC4118679  PMID: 23731166
case series models; exposure timing measurement error; hypothesis testing; inference; longitudinal observational database; non-homogeneous Poisson process
7.  Modeling Time Varying Effects with Generalized and Unsynchronized Longitudinal Data 
Statistics in medicine  2013;32(17):2971-2987.
Summary
We propose novel estimation approaches for generalized varying coefficient models that are tailored for unsynchronized, irregular and infrequent longitudinal designs/data. Unsynchronized longitudinal data refers to the time-dependent response and covariate measurements for each individual measured at distinct time points. The proposed methods are motivated by data from the Comprehensive Dialysis Study (CDS). We model the potential age-varying association between infection-related hospitalization status and the inflammatory marker, C-reactive protein (CRP), within the first two years from initiation of dialysis. Traditional longitudinal modeling cannot directly be applied to unsynchronized data and no method exists to estimate time- or age-varying effects for generalized outcomes (e.g., binary or count data) to date. In addition, through the analysis of the CDS data and simulation studies, we show that preprocessing steps, such as binning, needed to synchronize data to apply traditional modeling can lead to significant loss of information in this context. In contrast, the proposed approaches discard no observation; they exploit the fact that although there is little information in a single subject trajectory due to irregularity and infrequency, the moments of the underlying processes can be accurately and efficiently recovered by pooling information from all subjects using functional data analysis. Subject-specific mean response trajectory predictions are derived and finite sample properties of the estimators are studied.
doi:10.1002/sim.5740
PMCID: PMC3702655  PMID: 23335196
binning; functional data analysis; generalized linear models; sparse design; United States Renal Data System; varying coefficient models
8.  Sleep apnea in fragile X premutation carriers with and without FXTAS 
This report seeks to establish the prevalence of sleep apnea in patients with the FMR1 premutation with and without FXTAS and to determine any correlation between CGG repeat and FMR1 mRNA levels with sleep apnea prevalence. Demographic and medical data from 430 (229 males, 201 females) participants were used in this analysis. Participants included premutation carriers with (n=118) and without FXTAS (n=174) as well as controls without the premutation (n=123). Logistic regression models were employed to estimate the odds ratio of sleep apnea relative to controls, adjusted for age and gender, and also to examine potential association with CGG size and FMR1 mRNA expression level. The observed proportion of sleep apnea in premutation carriers with and without FXTAS and controls are 31.4% (37/118), 8.6% (15/174), and 13.8% (17/123), respectively. The adjusted odds of sleep apnea for premutation carriers with FXTAS is about 3.4 times that compared to controls (odds ratio, OR=3.4, 95% CI 1.8 to 7.4; p=0.001), and similarly relative to premutation carriers without FXTAS (OR=2.9, 95% CI 1.2 to 6.9; p=0.014). The risk of sleep apnea was not different between controls and premutation carriers without FXTAS. The presence of sleep apnea is not associated with CGG repeat numbers nor FMR1 mRNA expression level among premutation carriers. Our data supports a higher prevalence and risk of sleep apnea in patients with FXTAS. We recommend that all patients diagnosed with FXTAS be screened for sleep apnea given the negative and perhaps accelerative impact sleep apnea may have on their FXTAS progression.
doi:10.1002/ajmg.b.31237
PMCID: PMC4109408  PMID: 21932336
sleep apnea; fragile X-associated tremor/ataxia syndrome; trinucleotide repeat diseases; mitochondrial disorders; gait disorders/ataxia
9.  Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder 
Human genetics  2011;131(4):581-589.
Seizures are a common co-occurring condition in those with fragile X syndrome (FXS), and in those with idiopathic autism spectrum disorder (ASD). Seizures are also associated with ASD in those with FXS. However, little is known about the rate of seizures and how commonly these problems co-occur with ASD in boys with the FMR1 premutation. We, therefore, determined the prevalence of seizures and ASD in boys with the FMR1 permutation compared with their sibling counterparts and population prevalence estimates. Fifty premutation boys who presented as clinical probands (N = 25), or non-probands (identified by cascade testing after the proband was found) (N = 25), and 32 non-carrier controls were enrolled. History of seizures was documented and ASD was diagnosed by standardized measures followed by a team consensus of ASD diagnosis. Seizures (28%) and ASD (68%) were more prevalent in probands compared with non-probands (0 and 28%), controls (0 and 0%), and population estimates (1 and 1.7%). Seizures occurred more frequently in those with the premutation and co-morbid ASD particularly in probands compared with those with the premutation alone (25 vs. 3.85%, p = 0.045). Although cognitive and adaptive functioning in non-probands were similar to controls, non-probands were more likely to meet the diagnosis of ASD than controls (28 vs. 0%, p < 0.0001). In conclusion, seizures were relatively more common in premutation carriers who presented clinically as probands of the family and seizures were commonly associated with ASD in these boys. Therefore, boys with the premutation, particularly if they are probands should be assessed carefully for both ASD and seizures.
doi:10.1007/s00439-011-1106-6
PMCID: PMC4105134  PMID: 22001913
10.  Immune-mediated Disorders among Women Carrier of Fragile X Premutation Alleles 
The relative risk of immune-mediated disorders (IMDs) among women carrier of premutation alleles is estimated by a survey for IMDs among 344 carrier women (age 19 to 81 years; mean 46.35 and SD 12.60) and 72 controls (age 18 to 87 years; mean 52.40 and SD 15.40). One hundred fifty four (44.77%) women carrier had at least one IMD, as did 20 controls (27.78%). Among women carrier, autoimmune thyroid disorder was the most common (24.4%), then fibromyalgia (10.2%), irritable bowel syndrome (IBS; 9.9%), Raynaud’s phenomenon (7.6%), rheumatoid arthritis (RA; 3.8%), Sjögren syndrome (2.6%), systemic lupus erythematosus (SLE; 2.03%), multiple sclerosis (1.74%). Of 55 carriers age 40 or older with FXTAS, 72.73% had at least one IMD, compared to 46.54% of those without FXTAS (n=159), and 31.58% of controls (n=57). The estimated odds ratio (OR) for IMD is 2.6 (95% CI 1.2–5.6, p = 0.015) for women with FXTAS relative to those without FXTAS; the likelihood of IMD in carriers without or with FXTAS was also significantly higher than for controls (OR 2.1, 95% CI 1.1–4.2, p = 0.034; OR 5.5, 95% CI 2.4–12.5, p < 0.001 respectively). Similarly, the odds of having an IMD among carriers with FXPOI is about 2.4 times higher when compared to carriers without FXPOI (95% CI 1.1–5.0; p = 0.021). The likelihood of IMD in carriers with or without FXPOI is greater (OR 2.4, 95% CI 1.1–5.0; p = 0.021) compared to that of controls.
doi:10.1002/ajmg.a.35569
PMCID: PMC4105154  PMID: 22903889
Autoimmune; FXTAS; RNA toxicity; ovarian insufficiency
11.  Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers 
Objective
The authors studied the lifetime prevalence of DSM-IV-TR psychiatric disorders in a population of adults with the fragile X premutation.
Methods
Structured Clinical Interview for DSM-IV (SCID) were conducted on 85 individuals with the fragile X premutation, 47 with the fragile X-associated tremor/ataxia syndrome (FXTAS; 33 male, 14 female, mean age 66) and 38 without FXTAS (16 male, 22 female, mean age 52). Lifetime prevalence for mood and anxiety disorders among carriers with and without FXTAS was compared to available age-specific population estimates from the National Comorbidity Survey Replication (NCS-R).
Results
Among subjects with FXTAS, 30 cases (65%) met lifetime DSM-IV-TR criteria for mood disorder; 24 cases (52%) met lifetime DSM-IV-TR criteria for anxiety disorder. Among the non-FXTAS subjects, there were 15 cases (42%) of lifetime mood disorder and 18 cases (47%) of lifetime anxiety disorder. When compared to age-specific NCS-R data, the lifetime prevalence of any mood disorder, major depressive disorder, any anxiety disorder, panic disorder, specific phobia, and PTSD were significantly higher in subjects with FXTAS. The lifetime rates of social phobia in individuals with the premutation without FXTAS were significantly higher than NCS-R data.
Conclusions
This sample of carriers of the fragile X premutation had a notably high lifetime risk of mood and anxiety disorders. Mood and anxiety disorders may be part of the clinical phenotype of the fragile X premutation conditions, especially in carriers with FXTAS. Clinicians encountering these patients are advised to consider FXTAS as a neuropsychiatric syndrome as well as a neurological disorder.
doi:10.4088/JCP.09m05407blu
PMCID: PMC4038118  PMID: 20816038
Fragile X syndrome; fragile X-associated tremor/ataxia syndrome; FMR1 gene; (FXTAS); mood disorders; anxiety disorders
12.  Side Effects of Minocycline Treatment in Patients With Fragile X Syndrome and Exploration of Outcome Measures 
Minocycline can rescue the dendritic spine and synaptic structural abnormalities in the fragile X knock-out mouse. This is a review and preliminary survey to document side effects and potential outcome measures for minocycline use in the treatment of individuals with fragile X syndrome. We surveyed 50 patients with fragile X syndrome who received minocycline for at least 2 weeks and found that the most common reported side effect is gastrointestinal difficulty, including loss of appetite. The families reported an improvement in language and behavioral areas. Outcome measures in the design of future randomized clinical trials should include both behavioral and language measures. As with any other treatments, we emphasize that randomized clinical trials are needed to determine the efficacy of minocycline in fragile X syndrome.
doi:10.1352/1944-7558-115.5.433
PMCID: PMC4031088  PMID: 20687826
14.  Hypertension in FMR1 Premutation Males With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) 
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease that affects carriers of the fragile X premutation. This study seeks to assess hypertension risk and susceptibility in male premutation carriers with FXTAS. Although many symptoms and diagnostic criteria have been identified, hypertension risk has not been examined in this population. Data from 92 premutation carriers without FXTAS, 100 premutation carriers with FXTAS, and 186 controls was collected via patient medical interview. Age-adjusted logistic regression analysis was used to examine the relative odds of hypertension. We observed a significantly elevated odds ratio (OR) of hypertension relative to controls for premutation carriers with FXTAS (OR = 3.22, 95% CI: 1.72–6.04; P = 0.0003) among participants over 40-year old. The age-adjusted estimated odds of hypertension in premutation carriers without FXTAS in the over 40-year-old age group was higher compared to controls (OR = 1.61, 95% CI: 0.82–3.16), but was not statistically significant (P = 0.164). Chronic hypertension contributes to cardiovascular complications, dementia, and increased risk of stroke. Our results indicate that the risk of hypertension is significantly elevated in male premutation carriers with FXTAS compared with carriers without FXTAS and controls. Thus, evaluation of hypertension in patients diagnosed with FXTAS should be a routine part of the treatment monitoring and intervention for this disease.
doi:10.1002/ajmg.a.35323
PMCID: PMC3983689  PMID: 22528549
hypertension; FMR1 premutation; fragile X-associated tremor/ataxia syndrome; autonomic disease
15.  A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome 
Objective
Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial.
Method
Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment.
Results
Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared to placebo (2.49 ±0.13, 2.97 ±0.13, respectively, p 0.0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analoge Scale (minocycline 5.26 cm ±0.46 cm, placebo 4.05 cm±0.46cm; p 0.0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding and preliminary efficacy analysis results known to investigators.
Conclusion
Minocycline treatment for three months in children with FXS resulted in greater global improvement than placebo. Treatment for three months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.
doi:10.1097/DBP.0b013e318287cd17
PMCID: PMC3706260  PMID: 23572165
Fragile X Syndrome; Intellectual Disability; Minocycline; Matrix Metalloproteinase 9
16.  Early onset of neurological symptoms in fragile X premutation carriers exposed to neurotoxins 
Neurotoxicology  2010;31(4):399-402.
We present four cases of fragile X premutation carriers with early neurological symptoms, including symptoms consistent with multiple sclerosis (MS) and fragile X-associated tremor/ataxia syndrome (FXTAS). Each patient had significant exposure to one or more environmental neurotoxicants that have documented neurotoxicity (i.e. hexachlorocyclopentadiene or C56, Agent Orange, and 2,4- or 2,6-toluene diisocyanate and dichlormate). We hypothesize that premutation carriers are a vulnerable group to neurotoxins because elevated mRNA in the premutation can lead to early cell death and brain disease, leading to neuropsychiatric and neurological symptoms consistent with FXTAS.
doi:10.1016/j.neuro.2010.04.002
PMCID: PMC3918243  PMID: 20466021
Fragile X-associated tremor/ataxia; syndrome; Industrial chemical exposure; Premutation; FMR1; Hexachlorocyclopentadiene; Agent Orange
17.  Plasma cytokine profiles in Fragile X subjects: Is there a role for cytokines in the pathogenesis? 
Brain, behavior, and immunity  2010;24(6):898-902.
Background
Fragile X syndrome (FXS) is a single-gene disorder with a broad spectrum of involvement and a strong association with autism. Altered immune responses have been described in autism and there is potential that in children with FXS and autism, an abnormal immune response may play a role.
Objectives
To delineate specific patterns of cytokine/chemokine profiles in individuals with FXS with and without autism and to compare them with typical developing controls.
Methods
Age matched male subjects were recruited through the M.I.N.D. Institute and included: 19 typically developing controls, 64 subjects with FXS without autism and 40 subjects with FXS and autism. Autism diagnosis was confirmed with ADOS, ADI-R and DSM IV criteria. Plasma was isolated and cytokine and chemokine production was assessed by Luminex multiplex analysis.
Results
Preliminary observations indicate significant differences in plasma protein levels of a number of cytokines, including IL-1alpha, and the chemokines; RANTES and IP-10, between the FXS group and the typical developing controls (p<0.01). In addition, significant differences were observed between the FXS group with autism and the FXS without autism for IL-6, Eotaxin, MCP-1 (p<0.04).
Conclusions
In this study, the first of its kind, we report a significantly altered cytokine profile in FXS. The characterization of an immunological profile in FXS with and without autism may help to elucidate if an abnormal immune response may play a role and help to identify mechanisms important in the etiology of autism both with and without FXS.
doi:10.1016/j.bbi.2010.01.008
PMCID: PMC3626458  PMID: 20102735
Autism; Fragile X; cytokines; chemokines
18.  Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with Fragile X syndrome 
Genes, Brain, and Behavior  2012;11(3):332-341.
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and autism. The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA-binding protein linked to translational control. Recently, in the Fmr1 knockout mouse model of FXS, dysregulated translation initiation signaling was observed. To investigate whether an altered signaling was also a feature of subjects with FXS compared to typical developing controls, we isolated total RNA and translational control proteins from lymphocytes of subjects from both groups (38 FXS and 14 TD). Although we did not observe any difference in the expression level of mRNAs for translational initiation control proteins isolated from participant with FXS, we found increased phosphorylation of the mammalian target of rapamycin (mTOR) substrate, p70 ribosomal subunit 6 kinase1 (S6K1) and of the mTOR regulator, the serine/threonine protein kinase (Akt), in their protein lysates. In addition, we observed increased phosphorylation of the cap binding protein eukaryotic initiation factor 4E (eIF4E) suggesting that protein synthesis is upregulated in FXS. Similarly to the findings in lymphocytes, we observed increased phosphorylation of S6K1 in brain tissue from patients with FXS (n=6) compared to normal age matched controls (n=4). Finally, we detected increased expression of the cytoplasmic FMR1-interacting protein 2 (CYFIP2), a known FMRP interactor. This data verify and extend previous findings using lymphocytes for studies of neuropsychiatric disorders and provide evidence that misregulation of mTOR signaling observed in a FXS mouse model also occurs in human FXS and may provide useful biomarkers for designing target treatments in FXS.
doi:10.1111/j.1601-183X.2012.00768.x
PMCID: PMC3319643  PMID: 22268788
Fragile X; CYFIP1; CYFIP2; mTOR; phosphorylation
19.  Automated classification of fMRI during cognitive control identifies more severely disorganized subjects with schizophrenia 
Schizophrenia Research  2012;135(1-3):28-33.
The establishment of a neurobiologically based nosological system is one of the ultimate goals of modern biological psychiatry research. Developments in neuroimaging and statistical/machine learning have provided useful basic tools for these efforts. Recent studies have demonstrated the utility of fMRI as input data for the classification of schizophrenia, but none, to date, has used fMRI of cognitive control for this purpose. In this study, we evaluated the accuracy of an unbiased classification method on fMRI data from a large cohort of subjects with first episode schizophrenia and a cohort of age matched healthy control subjects while they completed the AX version of the Continuous Performance Task (AX-CPT). We compared these results to classifications based on AX-CPT behavioral data. Classification accuracy for DSM-IV defined schizophrenia using fMRI data was modest and comparable to classifications conducted with behavioral data. Interestingly fMRI classifications did however identify a distinct subgroup of patients with greater behavioral disorganization, whereas behavioral data classifications did not. These results suggest that fMRI-based classification could be a useful tool in defining a neurobiologically distinct subgroup within the clinically defined syndrome of schizophrenia, reflecting alterations in discrete neural circuits. Independent validation of classification-based phenotypes using other biological data such as genetics would provide a strong test of this hypothesis.
doi:10.1016/j.schres.2012.01.001
PMCID: PMC3288252  PMID: 22277668
Schizophrenia; fMRI; automated classification; nosology
20.  Sertraline May Improve Language Developmental Trajectory in Young Children with Fragile X Syndrome: A Retrospective Chart Review 
Autism Research and Treatment  2012;2012:104317.
Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12–50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS.
doi:10.1155/2012/104317
PMCID: PMC3420618  PMID: 22934167
21.  Infant siblings and the investigation of autism risk factors 
Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).
doi:10.1186/1866-1955-4-7
PMCID: PMC3436647  PMID: 22958474
Autism; Cohort; Epidemiology; Pregnancy; Prospective; Sibling; Study Design
22.  Sentinel Chicken Seroconversions Track Tangential Transmission of West Nile Virus to Humans in the Greater Los Angeles Area of California 
In Los Angeles, California, West Nile virus (WNV) has followed a pattern of emergence, amplification, subsidence, and resurgence. A time series cross-correlation analysis of human case counts and sentinel chicken seroconversions revealed temporal concordance indicating that chicken seroconversions tracked tangential transmission of WNV from the basic passeriform-Culex amplification cycle to humans rather than antecedent enzootic amplification. Sentinel seroconversions provided the location and time of transmission as opposed to human cases, which frequently were reported late and were assumed to be acquired 2–14 days before disease onset at their residence. Cox models revealed that warming degree-days were associated with the increased risk of seroconversion, whereas elevated herd immunity in peridomestic birds dampened seroconversion risk. Spatially, surveillance data collected within a 5 km radius of flock locations 15–28 days before the bleed date were most predictive of a seroconversion. In urban Los Angeles, sentinel chicken seroconversions could be used as an outcome measure in decision support for emergency intervention.
doi:10.4269/ajtmh.2010.10-0078
PMCID: PMC2963985  PMID: 21036853
23.  A consistent local linear estimator of the covariate adjusted correlation coefficient 
Statistics & probability letters  2009;79(15):1684-1689.
Consider the correlation between two random variables (X, Y), both not directly observed. One only observes X̃ = φ1(U)X + φ2(U) and Ỹ = ψ1(U)Y + ψ2(U), where all four functions {φl(·),ψl(·), l = 1, 2} are unknown/unspecified smooth functions of an observable covariate U. We consider consistent estimation of the correlation between the unobserved variables X and Y, adjusted for the above general dual additive and multiplicative effects of U, based on the observed data (X̃, Ỹ, U).
doi:10.1016/j.spl.2009.04.021
PMCID: PMC3124279  PMID: 21720454
Conditional correlation; Local method of moments; Nonparametric partial correlation; Nonparametric regression; Pearson correlation
24.  A Quantitative Assessment of Tremor and Ataxia in Female FMR1 Premutation Carriers Using CATSYS 
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a relatively common cause of balance problems leading to gait disturbances in older males (40%) with the premutation. FXTAS is less common in females. We utilized the CATSYS system, a quantitative measure of movement, in 23 women with FXTAS (mean age 62.7; SD 12.3), 90 women with the premutation without FXTAS (mean age 52.9; SD 9.4), and 37 controls (mean age 56.53; SD 7.8). CATSYS distinguished differences between carriers with and without FXTAS in postural tremor, postural sway, hand coordination, and reaction time tasks. Differences were also seen between carriers without FXTAS and controls in finger tapping, reaction time, and one postural sway task. However, these differences did not persist after statistical correction for multiple comparisons. Notably, there were no differences across groups in intention tremor. This is likely due to the milder symptoms in females compared to males with FXTAS.
doi:10.1155/2011/484713
PMCID: PMC3114433  PMID: 23008705
25.  Fibroblast phenotype in male carriers of FMR1 premutation alleles 
Human Molecular Genetics  2009;19(2):299-312.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55–200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as various forms of clinical involvement in carriers without FXTAS, are thought to arise through a direct toxic gain of function of high levels of FMR1 mRNA containing the expanded CGG repeat. Here we report a cellular endophenotype involving increased stress response (HSP27, HSP70 and CRYAB) and altered lamin A/C expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including six patients with FXTAS and five premutation carriers with no clinical evidence of FXTAS, compared with six controls. A similar abnormal cellular phenotype was found in CNS tissue from 10 patients with FXTAS. Finally, there is an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations are evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA triggers pathogenic mechanisms early in development, thus providing a molecular basis for the neurodevelopmental abnormalities observed in some children and clinical symptoms in some adults who are carriers of premutation FMR1 alleles. Cellular dysregulation in fibroblasts represents a novel and highly advantageous model for investigating disease pathogenesis in premutation carriers and for quantifying and monitoring disease progression. Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions.
doi:10.1093/hmg/ddp497
PMCID: PMC2796892  PMID: 19864489

Results 1-25 (33)