susan j ward - Academia.edu (original) (raw)
Papers by susan j ward
Neurology
Objective:To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for... more Objective:To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD).Methods:The consistency of changes in the six-minute walk distance (Δ6MWD) was compared across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented four sets of inclusion/exclusion criteria (n=383 patients, in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n=430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the trial's inclusion/exclusion criteria for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of pat...
PLOS ONE
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and c... more Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to � 5 at age~10y), 35% were in cluster 2 (NSAA � 5~12y), 21% in were cluster 3 (NSAA� 5~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement-or static behavior-by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease PLOS ONE | https://doi.org/10.1371/journal.pone.
![Research paper thumbnail of Corrigendum to "Categorizing natural history trajectories of ambulatory function measured by the 6-minute walk distance in patients with Duchenne muscular dystrophy" [Neuromuscular Disorders 26/9 (2016) 576-583]](https://attachments.academia-assets.com/66738898/thumbnails/1.jpg)
](Neuromuscular disorders : NMD, Jan 8, 2017
Neuromuscular Disorders, 2016
High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated ... more High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n = 25), moderate decline (n = 19), stable function (n = 37), and improving function (n = 15) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis.
Journal of Medicinal Chemistry, May 11, 1998
Journal of Pharmacology and Experimental Therapeutics
In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,94... more In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavio...
ChemInform, 1996
Aminoalkyl)indole Isothiocyanates as Potential Electrophilic Affinity Ligands for the Brain Canna... more Aminoalkyl)indole Isothiocyanates as Potential Electrophilic Affinity Ligands for the Brain Cannabinoid Receptor.
Endogenous and Exogenous Opiate Agonists and Antagonists, 1980
NIDA research monograph, 1990
... conclusion. It should be noted that the inhibition of adenylate cyclase by AAIs is via a G-pr... more ... conclusion. It should be noted that the inhibition of adenylate cyclase by AAIs is via a G-protein since the effect is GTP-dependent and pertussis toxin-sensitive (Pacheco et al., these proceedings). The ... Pharmacology, St. Louis University. 426
NIDA research monograph, 1990
NIDA research monograph, 1990
The Journal of pharmacology and experimental therapeutics, 1993
A binding assay for WIN 55212-2, an aminoalkylindole (AAI) with antinociceptive activity in roden... more A binding assay for WIN 55212-2, an aminoalkylindole (AAI) with antinociceptive activity in rodents, is described. [3H]WIN 55212-2 bound to rat cerebellar membranes with a Kd of 2 nM and a maximum binding of 1.2 pmol/mg of protein. Specific binding in this filtration assay was greater than 90%, saturable, reversible, stereospecific, pH sensitive and heat labile. Binding was decreased by Na+, K+, Li+ and nonhydrolyzable analogs of GTP and increased by Mg++ and Ca++. The density of specific binding sites varied throughout the central nervous system with the highest found in the cerebellum, hippocampus and striatum and the lowest in the medulla/pons and spinal cord. The binding affinities of other AAIs for the WIN 55212-2 binding site correlated with their potencies for inhibiting neuronally stimulated contractions in the isolated mouse vas deferens. Of more than 60 compounds representing recognized neurotransmitter systems, only cannabinoids effectively inhibited binding. The effect o...
Neurology
Objective:To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for... more Objective:To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD).Methods:The consistency of changes in the six-minute walk distance (Δ6MWD) was compared across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented four sets of inclusion/exclusion criteria (n=383 patients, in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n=430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the trial's inclusion/exclusion criteria for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of pat...
PLOS ONE
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and c... more Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that boys with DMD could be clustered into groups sharing similar trajectories of ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. We also explored associations with other variables such as age, functional abilities, and genotype. Using the NorthStar Clinical Network database, 395 patients with >1 NSAA assessment were identified. We utilised latent class trajectory analysis of longitudinal NSAA scores, which produced evidence for at least four clusters of boys sharing similar trajectories versus age in decreasing order of clinical severity: 25% of the boys were in cluster 1 (NSAA falling to � 5 at age~10y), 35% were in cluster 2 (NSAA � 5~12y), 21% in were cluster 3 (NSAA� 5~14y), and 19% in cluster 4 (NSAA > 5 up to 15y). Mean ages at diagnosis of DMD were similar across clusters (4.2, 3.9, 4.3, and 4.8y, respectively). However, at the first NSAA assessment, a significant (p<0.05) association was observed between earlier declining clusters and younger age, worse NSAA, slower rise from supine, slower 10 metre walk/run times, and younger age of steroid initiation. In order to assess the probability of observing complete loss of function for individual NSAA items, we examined the proportion of patients who shifted from a score of 1 or 2 at baseline to a score of 0. We also assessed the probability of gain of function using the inverse assessment and stratified the probability of deterioration, improvement-or static behavior-by age ranges and using baseline functional status. Using this tool, our study provides a comprehensive assessment of the NSAA in a large population of patients with DMD and, for the first time, describes discrete clusters of disease PLOS ONE | https://doi.org/10.1371/journal.pone.
Neuromuscular disorders : NMD, Jan 8, 2017
Neuromuscular Disorders, 2016
High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated ... more High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n = 25), moderate decline (n = 19), stable function (n = 37), and improving function (n = 15) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis.
Journal of Medicinal Chemistry, May 11, 1998
Journal of Pharmacology and Experimental Therapeutics
In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,94... more In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavio...
ChemInform, 1996
Aminoalkyl)indole Isothiocyanates as Potential Electrophilic Affinity Ligands for the Brain Canna... more Aminoalkyl)indole Isothiocyanates as Potential Electrophilic Affinity Ligands for the Brain Cannabinoid Receptor.
Endogenous and Exogenous Opiate Agonists and Antagonists, 1980
NIDA research monograph, 1990
... conclusion. It should be noted that the inhibition of adenylate cyclase by AAIs is via a G-pr... more ... conclusion. It should be noted that the inhibition of adenylate cyclase by AAIs is via a G-protein since the effect is GTP-dependent and pertussis toxin-sensitive (Pacheco et al., these proceedings). The ... Pharmacology, St. Louis University. 426
NIDA research monograph, 1990
NIDA research monograph, 1990
The Journal of pharmacology and experimental therapeutics, 1993
A binding assay for WIN 55212-2, an aminoalkylindole (AAI) with antinociceptive activity in roden... more A binding assay for WIN 55212-2, an aminoalkylindole (AAI) with antinociceptive activity in rodents, is described. [3H]WIN 55212-2 bound to rat cerebellar membranes with a Kd of 2 nM and a maximum binding of 1.2 pmol/mg of protein. Specific binding in this filtration assay was greater than 90%, saturable, reversible, stereospecific, pH sensitive and heat labile. Binding was decreased by Na+, K+, Li+ and nonhydrolyzable analogs of GTP and increased by Mg++ and Ca++. The density of specific binding sites varied throughout the central nervous system with the highest found in the cerebellum, hippocampus and striatum and the lowest in the medulla/pons and spinal cord. The binding affinities of other AAIs for the WIN 55212-2 binding site correlated with their potencies for inhibiting neuronally stimulated contractions in the isolated mouse vas deferens. Of more than 60 compounds representing recognized neurotransmitter systems, only cannabinoids effectively inhibited binding. The effect o...