Chloe O'Connell
Fellow in Anesthesiology, Perioperative and Pain Medicine
All Publications
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Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein.
The American journal of psychiatry
2018; 175 (3): 251–61
Abstract
Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials.The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single-nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression.The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes.These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices.
View details for PubMedID 29241359
View details for PubMedCentralID PMC5832545
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Preoperative depression, lumbar fusion, and opioid use: an assessment of postoperative prescription, quality, and economic outcomes.
Neurosurgical focus
2018; 44 (1): E5
Abstract
OBJECTIVE Preoperative depression has been linked to a variety of adverse outcomes following lumbar fusion, including increased pain, disability, and 30-day readmission rates. The goal of the present study was to determine whether preoperative depression is associated with increased narcotic use following lumbar fusion. Moreover, the authors examined the association between preoperative depression and a variety of secondary quality indicator and economic outcomes, including complications, 30-day readmissions, revision surgeries, likelihood of discharge home, and 1- and 2-year costs. METHODS A retrospective analysis was conducted using a national longitudinal administrative database (MarketScan) containing diagnostic and reimbursement data on patients with a variety of private insurance providers and Medicare for the period from 2007 to 2014. Multivariable logistic and negative binomial regressions were performed to assess the relationship between preoperative depression and the primary postoperative opioid use outcomes while controlling for demographic, comorbidity, and preoperative prescription drug-use variables. Logistic and log-linear regressions were also used to evaluate the association between depression and the secondary outcomes of complications, 30-day readmissions, revisions, likelihood of discharge home, and 1- and 2-year costs. RESULTS The authors identified 60,597 patients who had undergone lumbar fusion and met the study inclusion criteria, 4985 of whom also had a preoperative diagnosis of depression and 21,905 of whom had a diagnosis of spondylolisthesis at the time of surgery. A preoperative depression diagnosis was associated with increased cumulative opioid use (β = 0.25, p < 0.001), an increased risk of chronic use (OR 1.28, 95% CI 1.17-1.40), and a decreased probability of opioid cessation (OR 0.96, 95% CI 0.95-0.98) following lumbar fusion. In terms of secondary outcomes, preoperative depression was also associated with a slightly increased risk of complications (OR 1.14, 95% CI 1.03-1.25), revision fusions (OR 1.15, 95% CI 1.05-1.26), and 30-day readmissions (OR 1.19, 95% CI 1.04-1.36), although it was not significantly associated with the probability of discharge to home (OR 0.92, 95% CI 0.84-1.01). Preoperative depression also resulted in increased costs at 1 (β = 0.06, p < 0.001) and 2 (β = 0.09, p < 0.001) years postoperatively. CONCLUSIONS Although these findings must be interpreted in the context of the limitations inherent to retrospective studies utilizing administrative data, they provide additional evidence for the link between a preoperative diagnosis of depression and adverse outcomes, particularly increased opioid use, following lumbar fusion.
View details for DOI 10.3171/2017.10.FOCUS17563
View details for PubMedID 29290135
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Risk Prediction Models for Graft Failure after Liver Transplantation: A Machine-Learning Approach
WILEY. 2018: 668A–669A
View details for Web of Science ID 000446020501379
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Intraoperative analgesic regimens and surgical duration after spine surgery Response
NEUROSURGICAL FOCUS
2018; 45 (3)
View details for DOI 10.3171/2018.4.FOCUS18136
View details for Web of Science ID 000443301900013
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Geographic variation in the surgical management of lumbar spondylolisthesis: characterizing practice patterns and outcomes.
The spine journal : official journal of the North American Spine Society
2018
Abstract
The role of arthrodesis in the surgical management of lumbar spondylolisthesis remains controversial. We hypothesized that practice patterns and outcomes for this patient population may vary widely.To characterize geographic variation in surgical practices and outcomes for patients with lumbar spondylolisthesis.Retrospective analysis on a national longitudinal database between 2007 and 2014.We calculated arthrodesis rates, inpatient and long term costs, and key quality indicators (e.g. reoperation rates). Using linear and logistic regression models, we then calculated expected quality indicator values, adjusting for patient-level demographic factors, and compared these values to the observed values, to assess quality variation apart from differences in patient populations.We identified a cohort of 67,077 patients (60.7% female, mean age of 59.8 years (SD, 12.0) with lumbar spondylolisthesis who received either laminectomy or laminectomy with arthrodesis. The majority of patients received arthrodesis (91.8%). Actual rates of arthrodesis varied from 97.5% in South Dakota to 81.5% in Oregon. Geography remained a significant predictor of arthrodesis even after adjusting for demographic factors (p<0.001). Marked geographic variation was also observed in initial costs ($32,485 in Alabama to $78,433 in Colorado), two-year post-operative costs ($15,612 in Arkansas to $34,096 in New Jersey), length of hospital stay (2.6 days in Arkansas to 4.5 in Washington, D.C.), 30-day complication rates (9.5% in South Dakota to 22.4% in Maryland), 30-day readmission rates (2.5% in South Dakota to 13.6% in Connecticut), and reoperation rates (1.8% in Maine to 12.7% in Alabama).There is marked geographic variation in the rates of arthrodesis in treatment of spondylolisthesis within the United States. This variation remains pronounced after accounting for patient-level demographic differences. Costs of surgery and quality outcomes also vary widely. Further study is necessary to understand the drivers of this variation.
View details for PubMedID 29746964
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Postoperative Opioid Use, Complications, and Costs in Surgical Management of Lumbar Spondylolisthesis.
Spine
2017
Abstract
Retrospective analysis on a national longitudinal database (2007-2014).To determine the association between arthrodesis and complication rates, costs, surgical revision, and postoperative opioid prescription.Arthrodesis in patients receiving laminectomy for lumbar spondylolisthesis remains controversial. However, population-level evidence to support the use of arthrodesis remains limited.We identified 73,176 patient records and used coarsened exact matching to create comparable populations of patients who received laminectomy or laminectomy with arthrodesis. We use linear and logistic regression models to analyze the relationship between arthrodesis and postoperative complications, length of stay, costs, readmissions, surgical revisions, and postoperative opioid prescribing.Patients who underwent arthrodesis spent one more day in the hospital on average (p < 0.01), and had higher costs of care at their index visit ($24,126, p < 0.01), which were partially offset by lower costs of care over the two years following their procedure ($14,667 less in arthrodesis patients, p = 0.01). Patients with arthrodesis were less likely to have a surgical revision (OR = 0.66, p < 0.01). Patients with arthrodesis used more opioids in the first two months following their procedure, but had comparable opioid use to patients undergoing laminectomy without arthrodesis in all other post-operative months over the next two years, and were not more or less likely to convert to chronic opioid use. Postoperative opioid prescription varied dramatically across states (p < 0.01); geographic variation in opioid use is substantially greater than differences in opioid use based on procedure performed.Arthrodesis is associated with reduced likelihood of surgical revision and increased use of opioids in the first two months following surgery, but not associated with greater or lesser opioid use beyond the initial two postoperative months. Geographic variation in opioid use is substantial even after accounting for patient characteristics and for whether patients underwent arthrodesis.3.
View details for PubMedID 29215492
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Stop Signal Reaction Time Deficits in a Lifetime Obsessive-Compulsive Disorder Sample.
Journal of the International Neuropsychological Society
2016; 22 (7): 785-789
Abstract
Several studies have found impaired response inhibition, measured by a stop-signal task (SST), in individuals who are currently symptomatic for obsessive-compulsive disorder (OCD). The aim of this study was to assess stop-signal reaction time (SSRT) performance in individuals with a lifetime diagnosis of OCD, in comparison to a healthy control group. This is the first study that has examined OCD in participants along a continuum of OCD severity, including approximately half of whom had sub-syndromal symptoms at the time of assessment.OCD participants were recruited primarily from within the OCD clinic at a psychiatric hospital, as well as from the community. Healthy controls were recruited from the community. We used the stop signal task to examine the difference between 21 OCD participants (mean age, 42.95 years) and 40 healthy controls (mean age, 35.13 years). We also investigated the relationship between SST and measures of OCD, depression, and anxiety severity.OCD participants were significantly slower than healthy controls with regard to mean SSRT. Contrary to our prediction, there was no correlation between SSRT and current levels of OCD, anxiety, and depression severity.Results support prior studies showing impaired response inhibition in OCD, and extend the findings to a sample of patients with lifetime OCD who were not all currently above threshold for diagnosis. These findings indicate that response inhibition deficits may be a biomarker of OCD, regardless of current severity levels. (JINS, 2016, 22, 785-789).
View details for DOI 10.1017/S1355617716000540
View details for PubMedID 27334752
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DE NOVO MUTATIONS IN AUTISM IMPLICATE THE SYNAPTIC ELIMINATION NETWORK.
Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
2016; 22: 521-532
Abstract
Autism has been shown to have a major genetic risk component; the architecture of documented autism in families has been over and again shown to be passed down for generations. While inherited risk plays an important role in the autistic nature of children, de novo (germline) mutations have also been implicated in autism risk. Here we find that autism de novo variants verified and published in the literature are Bonferroni-significantly enriched in a gene set implicated in synaptic elimination. Additionally, several of the genes in this synaptic elimination set that were enriched in protein-protein interactions (CACNA1C, SHANK2, SYNGAP1, NLGN3, NRXN1, and PTEN) have been previously confirmed as genes that confer risk for the disorder. The results demonstrate that autism-associated de novos are linked to proper synaptic pruning and density, hinting at the etiology of autism and suggesting pathophysiology for downstream correction and treatment.
View details for PubMedID 27897003
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Extinction retention and fear renewal in a lifetime obsessive-compulsive disorder sample.
Behavioural brain research
2015; 280: 72-77
Abstract
Obsessive-compulsive disorder (OCD), like other illnesses with prominent anxiety, may involve abnormal fear regulation and consolidation of safety memories. Impaired fear extinction memory (extinction recall, ER) has been shown in individuals with current symptoms of OCD [1]. However, contrary to expectations, the only previous study investigating this phenomenon showed a positive correlation between extinction recall abilities and OCD symptomology (i.e., as OCD symptoms worsened, extinction memory improved). The purpose of the current study was to determine if patients with a lifetime diagnosis of OCD (not necessarily currently symptomatic) also demonstrate impairments in extinction memory, and the relationship between OCD symptomology and extinction memory in this type of sample. In addition, we also examined fear renewal, which has never been investigated in an OCD sample. We enrolled 37 patients with OCD, the majority of whom were on serotonin reuptake inhibitors, and 18 healthy control participants in a 2-day paradigm assessing fear conditioning and extinction (Day 1) and extinction retention and renewal (Day 2). Skin conductance responses (SCRs) were the dependent measure. Results, as in the prior study, indicated that the only between-group difference was impaired ER in OCD patients relative to controls. Contrary to our prediction, OCD symptom severity was not correlated with the magnitude of extinction recall. There were no differences in fear renewal between OCD patients and controls.
View details for DOI 10.1016/j.bbr.2014.11.011
View details for PubMedID 25446749
View details for PubMedCentralID PMC4596815
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Ion channels and schizophrenia: a gene set-based analytic approach to GWAS data for biological hypothesis testing
HUMAN GENETICS
2012; 131 (3): 373-391
Abstract
Schizophrenia is a complex genetic disorder. Gene set-based analytic (GSA) methods have been widely applied for exploratory analyses of large, high-throughput datasets, but less commonly employed for biological hypothesis testing. Our primary hypothesis is that variation in ion channel genes contribute to the genetic susceptibility to schizophrenia. We applied Exploratory Visual Analysis (EVA), one GSA application, to analyze European-American (EA) and African-American (AA) schizophrenia genome-wide association study datasets for statistical enrichment of ion channel gene sets, comparing GSA results derived under three SNP-to-gene mapping strategies: (1) GENIC; (2) 500-Kb; (3) 2.5-Mb and three complimentary SNP-to-gene statistical reduction methods: (1) minimum p value (pMIN); (2) a novel method, proportion of SNPs per Gene with p values below a pre-defined α-threshold (PROP); and (3) the truncated product method (TPM). In the EA analyses, ion channel gene set(s) were enriched under all mapping and statistical approaches. In the AA analysis, ion channel gene set(s) were significantly enriched under pMIN for all mapping strategies and under PROP for broader mapping strategies. Less extensive enrichment in the AA sample may reflect true ethnic differences in susceptibility, sampling or case ascertainment differences, or higher dimensionality relative to sample size of the AA data. More consistent findings under broader mapping strategies may reflect enhanced power due to increased SNP inclusion, enhanced capture of effects over extended haplotypes or significant contributions from regulatory regions. While extensive pMIN findings may reflect gene size bias, the extent and significance of PROP and TPM findings suggest that common variation at ion channel genes may capture some of the heritability of schizophrenia.
View details for DOI 10.1007/s00439-011-1082-x
View details for Web of Science ID 000300252700006
View details for PubMedID 21866342
View details for PubMedCentralID PMC3278516