Previous studies of air pollution and birth outcomes have not evaluated whether complicated pregn... more Previous studies of air pollution and birth outcomes have not evaluated whether complicated pregnancies might be susceptible to the adverse effects of air pollution. It was hypothesised that trimester mean pollutant concentrations could be associated with fetal growth restriction, with larger risks among complicated pregnancies. A multiyear linked birth certificate and maternal/newborn hospital discharge dataset of singleton, term births to mothers residing in New Jersey at the time of birth, who were white (non-Hispanic), African-American (non-Hispanic) or Hispanic was used. Very small for gestational age (VSGA) was defined as a fetal growth ratio <0.75, small for gestational age (SGA) as > or =0.75 and <0.85, and 'reference' births as > or =0.85. Using polytomous logistic regression, associations between mean pollutant concentrations during the first, second and third trimesters and the risks of SGA/VSGA were examined, as well as effect modification of these associations by several pregnancy complications. Significantly increased risk of SGA was associated with first and third trimester PM(2.5) (particulate matter <2.5 microm in aerodynamic diameter), and increased risk of VSGA associated with first, second and third trimester nitrogen dioxide (NO(2)) concentrations. Pregnancies complicated by placental abruption and premature rupture of the membrane had approximately two- to fivefold greater excess risks of SGA/VSGA than pregnancies not complicated by these conditions, although these estimates were not statistically significant. These findings suggest that ambient air pollution, perhaps specifically traffic emissions during early and late pregnancy and/or factors associated with residence near a roadway during pregnancy, may affect fetal growth. Further, pregnancy complications may increase susceptibility to these effects in late pregnancy.
Evaluation of the therapy of X-linked adrenoleukodystrophy (X-ALD) is hampered by its rarity and ... more Evaluation of the therapy of X-linked adrenoleukodystrophy (X-ALD) is hampered by its rarity and by the striking and unpredictable variation in phenotypic expression. We present two approaches that may facilitate therapy evaluation. (1) We have analysed data on 377 X-ALD patients who have been followed at the Kennedy Krieger Institute for a mean period of 38 months and have subdivided them into 18 subgroups on the basis of age and the degree of abnormality in brain magnetic resonance imaging (MRI) as assessed by the Loes score (Am. J. Neuroradrol 1994; 15: 1761). We find that grouping on the basis of age and MRI score provides information that is of significant prognostic value. (2) We present plans for the development of a placebo-controlled multicentre international study that will have sufficient biostatistical power to provide objective evaluation of new therapeutic interventions.
Following the World Trade Center disaster, a large number of individuals involved in rescue and r... more Following the World Trade Center disaster, a large number of individuals involved in rescue and recovery activity were exposed to significant amounts of dust, and reported symptoms of chronic nasal and sinus inflammation. An unusually high prevalence of obstructive sleep apnea (OSA) has also been observed in this World Trade Center Responder population. This project aims to examine the relationship between nasal pathology and OSA. Our hypothesis is that increased nasal resistance due to nasal inflammation predisposes to OSA in this population. Continuous Positive Airway Pressure (CPAP) is the standard therapy for OSA but despite its efficacy has poor adherence. Subjects with high nasal resistance may have greater difficulty in tolerating this therapy than those who do not have high nasal resistance. Reduction of excess expiratory positive pressure by the modality known as Cflexâ„¢ during Continuous Positive Airway Pressure therapy (CPAPFlex) has been suggested to improve comfort without compromising efficacy. We will compare CPAP to CPAPFlex in subjects with OSA. Subjects with new onset habitual snoring will be screened for OSA using home sleep studies and rhinomanometry will be used to determine nasal resistance. In 400 subjects with OSA we will perform a randomized double blind cross-over study comparing CPAP to CPAPflex, and relate nasal resistance to adherence to CPAP therapy. This is the first multicenter trial designed to test the hypothesis that adherence to CPAP therapy relates to nasal resistance and CPAPFlex will improve adherence to CPAP in those subjects with high nasal resistance. We anticipate the following results from this trial: 1. Increased nasal resistance is associated with decreased adherence to CPAP therapy. 2. Use of CPAPFlex improves adherence with CPAP therapy in subjects with high nasal resistance, but not in those with low nasal resistance. 3. The benefit of CPAPFlex on adherence is greatest when offered at CPAP therapy initiation rather than as a "rescue" therapy in subjects with high nasal resistance. ClinicalTrials.gov Identifier: NCT01753999 , Date: 12 December 2012.
To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier... more To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.6...
We evaluated the effectiveness of heart rate variability (HRV) biofeedback as a complementary tre... more We evaluated the effectiveness of heart rate variability (HRV) biofeedback as a complementary treatment for asthma. Ninety-four adult outpatient paid volunteers with asthma. The psychophysiology laboratory at The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, and the private outpatient offices of participating asthma physicians. The interventions were as follows: (1) a full protocol (ie, HRV biofeedback and abdominal breathing through pursed lips and prolonged exhalation); (2) HRV biofeedback alone; (3) placebo EEG biofeedback; and (4) a waiting list control. Subjects were first prestabilized using controller medication and then were randomly assigned to experimental groups. Medication was titrated biweekly by blinded asthma specialists according to a protocol based on National Heart, Lung, and Blood Institute guidelines, according to symptoms, spirometry, and home peak flows. Subjects recorded daily asthma symptoms and twice-daily peak expira...
The purpose of this study was to examine the rate of psychiatric disorders among patients attendi... more The purpose of this study was to examine the rate of psychiatric disorders among patients attending an ethnically diverse, inner-city asthma clinic for an initial visit and assess the association between psychiatric disorders and asthma morbidity. A semistructured psychological interview was conducted to assess for psychiatric diagnoses. A pulmonary physician, who was blind to psychiatric disorder, established diagnosis of asthma based on national guidelines. Sixty-four percent of 85 participants received at least 1 psychiatric diagnosis. The pulmonary physician rated patients with a psychiatric disorder as achieving fewer goals (M = 2.3 +/- 1.3) for asthma control than patients without a psychiatric disorder (M = 3.6 +/- 1.5, p = .0002). Patients with a psychiatric diagnosis more frequently reported an emergency room visit for asthma during the past 6 months (OR = 4.89; 95% CI, 1.76-13.39) and greater use of short-acting beta2-agonist medication (M = 1.5 +/- 0.9 canisters per month) than patients without a psychiatric diagnosis (M = 0.9 +/- 0.8, p = .003). These findings were independent of demographics, health insurance, and asthma severity. No differences emerged between patients with and without a mental disorder on percent predicted FEV1. Patients with a psychiatric disorder reported a higher severity level for asthma symptoms than the severity level indicated by their pulmonary function in comparison to patients without a psychiatric diagnosis (OR = 3.52; 95% CI, 1.23-10.10). Health insurance appeared to be a confounding factor in this relationship. A high rate of psychiatric disorders was found among inner-city asthma patients. Psychiatric diagnoses were associated with greater perceived impairment from asthma but not objective measurement of pulmonary function.
Severe injury and infection are associated with autonomic dysfunction. Diminished heart rate vari... more Severe injury and infection are associated with autonomic dysfunction. Diminished heart rate variability (HRV) is also observed as a component of autonomic dysfunction and is induced by endotoxin administration to healthy subjects. It is established that low-dose glucocorticoid administration diminishes the systemic inflammatory manifestations of endotoxinemia but the influence of this anti-inflammatory intervention on overall autonomic dysfunction and HRV responses to endotoxin is unknown. This study was designed to assess the influence of a low-dose hydrocortisone infusion upon endotoxin-elicited systemic inflammatory responses including phenotypic features, cytokine production, and parameters of HRV. Of 19 subjects studied, nine received a continuous infusion of hydrocortisone (3 microg/kg/min continuously over 6 h) prior to intravenous administration of Escherichia coli endotoxin (2 ng/kg, CC-RE, Lot #2) while 10 healthy subjects received only the endotoxin after a 6-h period of...
The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progre... more The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. This study reports on 372 patients ranging in age from less than 3 years to adulthood, who have been followed at the Kennedy Krieger Institute. With the aim of determining whether a method could be developed to predict clinical course by analysis of data available at time of first contact, the patients were subdivided into 18 subgroups on the basis of age and the extent of brain magnetic resonance (MRI) abnormality utilizing the MRI scoring system devised by Loes et al. Scores to grade degree of neurologic and neuropsychologic impairment were also developed. There was strong correlation between MRI and the neurology and neuropsychology scores at baseline. Information based exclusively on age and MRI score at time of first contact was highly predictive of future clinical course and should aid the evaluation of the effects of bone marrow transplantation and the selection of patients for this procedure, as well as the evaluation of other therapies that may be developed in the future.
Journal of Clinical Child & Adolescent Psychology, 2007
This study evaluated the relationship between threat perception bias and anxiety among children a... more This study evaluated the relationship between threat perception bias and anxiety among children and adolescents in China. A sample of 1,004 elementary, middle and high school students aged 9 to 19 years listened to stories containing themes of generalized anxiety, social anxiety and separation anxiety in either an ambiguous or non-ambiguous context. The story content included topics such as upset stomach, teacher-student interaction, and parents who are late to return home. Multiple threat perception indices were derived from children's responses. Children's level of anxiety was assessed by means of self-report questionnaires and parental reports. Higher levels of anxiety were related to higher frequencies of threat perception and interpretation, lower thresholds to detect threat and more negative feelings and cognitions. Age and gender were also related to some indices of threat perception bias. Threat perception bias was related to anxious symptomatology in general and was not content specific to particular anxiety disorders. The findings were consistent with studies conducted in Western culture and suggest that cognitive processing theories of childhood anxiety may generalize beyond Western society.
Multi-level clustered failure time data arise when the clustering of data occurs at more than one... more Multi-level clustered failure time data arise when the clustering of data occurs at more than one level. It is of interest to estimate the relative risks of covariates and clustering effect of failure times at each level. We consider a nested random effect proportional hazards model, where a subcluster-specific frailty operates multiplicatively on the conditional hazard model, and its distribution
We consider the problem of estimating covariate effects in the marginal Cox proportional hazard m... more We consider the problem of estimating covariate effects in the marginal Cox proportional hazard model and multilevel associations for child mortality data collected from a vitamin A supplementation trial in Nepal, where the data are clustered within households and villages. For this purpose, a class of multivariate survival models that can be represented by a functional of marginal survival functions and accounts for hierarchical structure of clustering is exploited. Based on this class of models, an estimation strategy involving a within-cluster resampling procedure is proposed, and a model assessment approach is presented. The asymptotic theory for the proposed estimators and lack-of-fit test is established. The simulation study shows that the estimates are approximately unbiased, and the proposed test statistic is conservative under extremely heavy censoring but approaches the size otherwise. The analysis of the Nepal study data shows that the association of mortality is much greater within households than within villages.
Previous studies of air pollution and birth outcomes have not evaluated whether complicated pregn... more Previous studies of air pollution and birth outcomes have not evaluated whether complicated pregnancies might be susceptible to the adverse effects of air pollution. It was hypothesised that trimester mean pollutant concentrations could be associated with fetal growth restriction, with larger risks among complicated pregnancies. A multiyear linked birth certificate and maternal/newborn hospital discharge dataset of singleton, term births to mothers residing in New Jersey at the time of birth, who were white (non-Hispanic), African-American (non-Hispanic) or Hispanic was used. Very small for gestational age (VSGA) was defined as a fetal growth ratio <0.75, small for gestational age (SGA) as > or =0.75 and <0.85, and 'reference' births as > or =0.85. Using polytomous logistic regression, associations between mean pollutant concentrations during the first, second and third trimesters and the risks of SGA/VSGA were examined, as well as effect modification of these associations by several pregnancy complications. Significantly increased risk of SGA was associated with first and third trimester PM(2.5) (particulate matter <2.5 microm in aerodynamic diameter), and increased risk of VSGA associated with first, second and third trimester nitrogen dioxide (NO(2)) concentrations. Pregnancies complicated by placental abruption and premature rupture of the membrane had approximately two- to fivefold greater excess risks of SGA/VSGA than pregnancies not complicated by these conditions, although these estimates were not statistically significant. These findings suggest that ambient air pollution, perhaps specifically traffic emissions during early and late pregnancy and/or factors associated with residence near a roadway during pregnancy, may affect fetal growth. Further, pregnancy complications may increase susceptibility to these effects in late pregnancy.
Evaluation of the therapy of X-linked adrenoleukodystrophy (X-ALD) is hampered by its rarity and ... more Evaluation of the therapy of X-linked adrenoleukodystrophy (X-ALD) is hampered by its rarity and by the striking and unpredictable variation in phenotypic expression. We present two approaches that may facilitate therapy evaluation. (1) We have analysed data on 377 X-ALD patients who have been followed at the Kennedy Krieger Institute for a mean period of 38 months and have subdivided them into 18 subgroups on the basis of age and the degree of abnormality in brain magnetic resonance imaging (MRI) as assessed by the Loes score (Am. J. Neuroradrol 1994; 15: 1761). We find that grouping on the basis of age and MRI score provides information that is of significant prognostic value. (2) We present plans for the development of a placebo-controlled multicentre international study that will have sufficient biostatistical power to provide objective evaluation of new therapeutic interventions.
Following the World Trade Center disaster, a large number of individuals involved in rescue and r... more Following the World Trade Center disaster, a large number of individuals involved in rescue and recovery activity were exposed to significant amounts of dust, and reported symptoms of chronic nasal and sinus inflammation. An unusually high prevalence of obstructive sleep apnea (OSA) has also been observed in this World Trade Center Responder population. This project aims to examine the relationship between nasal pathology and OSA. Our hypothesis is that increased nasal resistance due to nasal inflammation predisposes to OSA in this population. Continuous Positive Airway Pressure (CPAP) is the standard therapy for OSA but despite its efficacy has poor adherence. Subjects with high nasal resistance may have greater difficulty in tolerating this therapy than those who do not have high nasal resistance. Reduction of excess expiratory positive pressure by the modality known as Cflexâ„¢ during Continuous Positive Airway Pressure therapy (CPAPFlex) has been suggested to improve comfort without compromising efficacy. We will compare CPAP to CPAPFlex in subjects with OSA. Subjects with new onset habitual snoring will be screened for OSA using home sleep studies and rhinomanometry will be used to determine nasal resistance. In 400 subjects with OSA we will perform a randomized double blind cross-over study comparing CPAP to CPAPflex, and relate nasal resistance to adherence to CPAP therapy. This is the first multicenter trial designed to test the hypothesis that adherence to CPAP therapy relates to nasal resistance and CPAPFlex will improve adherence to CPAP in those subjects with high nasal resistance. We anticipate the following results from this trial: 1. Increased nasal resistance is associated with decreased adherence to CPAP therapy. 2. Use of CPAPFlex improves adherence with CPAP therapy in subjects with high nasal resistance, but not in those with low nasal resistance. 3. The benefit of CPAPFlex on adherence is greatest when offered at CPAP therapy initiation rather than as a "rescue" therapy in subjects with high nasal resistance. ClinicalTrials.gov Identifier: NCT01753999 , Date: 12 December 2012.
To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier... more To examine whether the presence of sleep-disordered breathing (SDB) is associated with an earlier age at mild cognitive impairment (MCI) or Alzheimer disease (AD)-dementia onset in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We also examined whether continuous positive airway pressure (CPAP) use is associated with delayed onset of cognitive decline. From the ADNI cohort, 3 subsets with progressively stringent criteria were created in a step-wise manner. Age at MCI or AD-dementia onset was the main outcome variable. Analyses were performed separately for each subset in untreated SDB+ vs SDB- and untreated SDB+ vs CPAP+ groups. Chi-square and t tests were performed to examine between-group differences. Survival analyses were performed using the Kaplan-Meier method, compared by the log-rank test, and assessed by multivariate Cox regression adjusting for potential confounders. SDB+ patients had a younger age at MCI onset in all subsets (MC1: 72.6...
We evaluated the effectiveness of heart rate variability (HRV) biofeedback as a complementary tre... more We evaluated the effectiveness of heart rate variability (HRV) biofeedback as a complementary treatment for asthma. Ninety-four adult outpatient paid volunteers with asthma. The psychophysiology laboratory at The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, and the private outpatient offices of participating asthma physicians. The interventions were as follows: (1) a full protocol (ie, HRV biofeedback and abdominal breathing through pursed lips and prolonged exhalation); (2) HRV biofeedback alone; (3) placebo EEG biofeedback; and (4) a waiting list control. Subjects were first prestabilized using controller medication and then were randomly assigned to experimental groups. Medication was titrated biweekly by blinded asthma specialists according to a protocol based on National Heart, Lung, and Blood Institute guidelines, according to symptoms, spirometry, and home peak flows. Subjects recorded daily asthma symptoms and twice-daily peak expira...
The purpose of this study was to examine the rate of psychiatric disorders among patients attendi... more The purpose of this study was to examine the rate of psychiatric disorders among patients attending an ethnically diverse, inner-city asthma clinic for an initial visit and assess the association between psychiatric disorders and asthma morbidity. A semistructured psychological interview was conducted to assess for psychiatric diagnoses. A pulmonary physician, who was blind to psychiatric disorder, established diagnosis of asthma based on national guidelines. Sixty-four percent of 85 participants received at least 1 psychiatric diagnosis. The pulmonary physician rated patients with a psychiatric disorder as achieving fewer goals (M = 2.3 +/- 1.3) for asthma control than patients without a psychiatric disorder (M = 3.6 +/- 1.5, p = .0002). Patients with a psychiatric diagnosis more frequently reported an emergency room visit for asthma during the past 6 months (OR = 4.89; 95% CI, 1.76-13.39) and greater use of short-acting beta2-agonist medication (M = 1.5 +/- 0.9 canisters per month) than patients without a psychiatric diagnosis (M = 0.9 +/- 0.8, p = .003). These findings were independent of demographics, health insurance, and asthma severity. No differences emerged between patients with and without a mental disorder on percent predicted FEV1. Patients with a psychiatric disorder reported a higher severity level for asthma symptoms than the severity level indicated by their pulmonary function in comparison to patients without a psychiatric diagnosis (OR = 3.52; 95% CI, 1.23-10.10). Health insurance appeared to be a confounding factor in this relationship. A high rate of psychiatric disorders was found among inner-city asthma patients. Psychiatric diagnoses were associated with greater perceived impairment from asthma but not objective measurement of pulmonary function.
Severe injury and infection are associated with autonomic dysfunction. Diminished heart rate vari... more Severe injury and infection are associated with autonomic dysfunction. Diminished heart rate variability (HRV) is also observed as a component of autonomic dysfunction and is induced by endotoxin administration to healthy subjects. It is established that low-dose glucocorticoid administration diminishes the systemic inflammatory manifestations of endotoxinemia but the influence of this anti-inflammatory intervention on overall autonomic dysfunction and HRV responses to endotoxin is unknown. This study was designed to assess the influence of a low-dose hydrocortisone infusion upon endotoxin-elicited systemic inflammatory responses including phenotypic features, cytokine production, and parameters of HRV. Of 19 subjects studied, nine received a continuous infusion of hydrocortisone (3 microg/kg/min continuously over 6 h) prior to intravenous administration of Escherichia coli endotoxin (2 ng/kg, CC-RE, Lot #2) while 10 healthy subjects received only the endotoxin after a 6-h period of...
The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progre... more The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy (AMN) in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. This study reports on 372 patients ranging in age from less than 3 years to adulthood, who have been followed at the Kennedy Krieger Institute. With the aim of determining whether a method could be developed to predict clinical course by analysis of data available at time of first contact, the patients were subdivided into 18 subgroups on the basis of age and the extent of brain magnetic resonance (MRI) abnormality utilizing the MRI scoring system devised by Loes et al. Scores to grade degree of neurologic and neuropsychologic impairment were also developed. There was strong correlation between MRI and the neurology and neuropsychology scores at baseline. Information based exclusively on age and MRI score at time of first contact was highly predictive of future clinical course and should aid the evaluation of the effects of bone marrow transplantation and the selection of patients for this procedure, as well as the evaluation of other therapies that may be developed in the future.
Journal of Clinical Child & Adolescent Psychology, 2007
This study evaluated the relationship between threat perception bias and anxiety among children a... more This study evaluated the relationship between threat perception bias and anxiety among children and adolescents in China. A sample of 1,004 elementary, middle and high school students aged 9 to 19 years listened to stories containing themes of generalized anxiety, social anxiety and separation anxiety in either an ambiguous or non-ambiguous context. The story content included topics such as upset stomach, teacher-student interaction, and parents who are late to return home. Multiple threat perception indices were derived from children's responses. Children's level of anxiety was assessed by means of self-report questionnaires and parental reports. Higher levels of anxiety were related to higher frequencies of threat perception and interpretation, lower thresholds to detect threat and more negative feelings and cognitions. Age and gender were also related to some indices of threat perception bias. Threat perception bias was related to anxious symptomatology in general and was not content specific to particular anxiety disorders. The findings were consistent with studies conducted in Western culture and suggest that cognitive processing theories of childhood anxiety may generalize beyond Western society.
Multi-level clustered failure time data arise when the clustering of data occurs at more than one... more Multi-level clustered failure time data arise when the clustering of data occurs at more than one level. It is of interest to estimate the relative risks of covariates and clustering effect of failure times at each level. We consider a nested random effect proportional hazards model, where a subcluster-specific frailty operates multiplicatively on the conditional hazard model, and its distribution
We consider the problem of estimating covariate effects in the marginal Cox proportional hazard m... more We consider the problem of estimating covariate effects in the marginal Cox proportional hazard model and multilevel associations for child mortality data collected from a vitamin A supplementation trial in Nepal, where the data are clustered within households and villages. For this purpose, a class of multivariate survival models that can be represented by a functional of marginal survival functions and accounts for hierarchical structure of clustering is exploited. Based on this class of models, an estimation strategy involving a within-cluster resampling procedure is proposed, and a model assessment approach is presented. The asymptotic theory for the proposed estimators and lack-of-fit test is established. The simulation study shows that the estimates are approximately unbiased, and the proposed test statistic is conservative under extremely heavy censoring but approaches the size otherwise. The analysis of the Nepal study data shows that the association of mortality is much greater within households than within villages.
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Papers by Shou-en Lu