Dataset Information

Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury.

ABSTRACT: Genetic association analyses suggest that certain common single nucleotide polymorphisms (SNPs) may adversely impact recovery from traumatic brain injury (TBI). Delineating their causal relationship may aid in development of novel interventions and in identifying patients likely to respond to targeted therapies. We examined the influence of the (C/T) SNP rs1800497 of ANKK1 on post-TBI outcome using data from two prospective multicenter studies: the Citicoline Brain Injury Treatment (COBRIT) trial and Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot). We included patients with ANKK1 genotyping results and cognitive outcomes at six months post-TBI (n?=?492: COBRIT n?=?272, TRACK-TBI Pilot n?=?220). Using the California Verbal Learning Test Second Edition (CVLT-II) Trial 1-5 Standard Score, we found a dose-dependent effect for the T allele, with T/T homozygotes scoring lowest on the CVLT-II Trial 1-5 Standard Score (T/T 45.1, C/T 51.1, C/C 52.1, ANOVA, p?=?0.008). Post hoc testing with multiple comparison-correction indicated that T/T patients performed significantly worse than C/T and C/C patients. Similar effects were observed in a test of non-verbal processing (Wechsler Adult Intelligence Scale, Processing Speed Index). Our findings extend those of previous studies reporting a negative relationship of the ANKK1 T allele with cognitive performance after TBI. In this study, we demonstrate the value of pooling shared clinical, biomarker, and outcome variables from two large datasets applying the NIH TBI Common Data Elements. The results have implications for future multicenter investigations to further elucidate the role of ANKK1 in post-TBI outcome.

SUBMITTER: Yue JK

PROVIDER: S-EPMC5588885 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury.

Yue John K JK Pronger Angela M AM Ferguson Adam R AR Temkin Nancy R NR Sharma Sourabh S Rosand Jonathan J Sorani Marco D MD McAllister Thomas W TW Barber Jason J Winkler Ethan A EA Burchard Esteban G EG Hu Donglei D Lingsma Hester F HF Cooper Shelly R SR Puccio Ava M AM Okonkwo David O DO Diaz-Arrastia Ramon R Manley Geoffrey T GT

Neurogenetics 20150130 3

Genetic association analyses suggest that certain common single nucleotide polymorphisms (SNPs) may adversely impact recovery from traumatic brain injury (TBI). Delineating their causal relationship may aid in development of novel interventions and in identifying patients likely to respond to targeted therapies. We examined the influence of the (C/T) SNP rs1800497 of ANKK1 on post-TBI outcome using data from two prospective multicenter studies: the Citicoline Brain Injury Treatment (COBRIT) tria ...[more]

PMID: 25633559

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Project description:INTRODUCTION: The aim of this study was to evaluate the usefulness of the APACHE II (Acute Physiology and Chronic Health Evaluation II), SAPS II (Simplified Acute Physiology Score II) and SOFA (Sequential Organ Failure Assessment) scores compared to simpler models based on age and Glasgow Coma Scale (GCS) in predicting long-term outcome of patients with moderate-to-severe traumatic brain injury (TBI) treated in the intensive care unit (ICU). METHODS: A national ICU database was screened for eligible TBI patients (age over 15 years, GCS 3-13) admitted in 2003-2012. Logistic regression was used for customization of APACHE II, SAPS II and SOFA score-based models for six-month mortality prediction. These models were compared to an adjusted SOFA-based model (including age) and a reference model (age and GCS). Internal validation was performed by a randomized split-sample technique. Prognostic performance was determined by assessing discrimination, calibration and precision. RESULTS: In total, 1,625 patients were included. The overall six-month mortality was 33%. The APACHE II and SAPS II-based models showed good discrimination (area under the curve (AUC) 0.79, 95% confidence interval (CI) 0.75 to 0.82; and 0.80, 95% CI 0.77 to 0.83, respectively), calibration (P?>?0.05) and precision (Brier score 0.166 to 0.167). The SOFA-based model showed poor discrimination (AUC 0.68, 95% CI 0.64 to 0.72) and precision (Brier score 0.201) but good calibration (P?>?0.05). The AUC of the SOFA-based model was significantly improved after the insertion of age and GCS (?AUC +0.11, P?<?0.001). The performance of the reference model was comparable to the APACHE II and SAPS II in terms of discrimination (AUC 0.77; compared to APACHE II, ?AUC -0.02, P?=?0.425; compared to SAPS II, ?AUC -0.03, P?=?0.218), calibration (P?>?0.05) and precision (Brier score 0.181). CONCLUSIONS: A simple prognostic model, based only on age and GCS, displayed a fairly good prognostic performance in predicting six-month mortality of ICU-treated patients with TBI. The use of the more complex scoring systems APACHE II, SAPS II and SOFA added little to the prognostic performance.

Project description:Cross-sectional approaches to outcome assessment may not adequately capture heterogeneity in recovery after traumatic brain injury (TBI). Using latent class mixed models (LCMM), a data-driven analytic that identifies groups of patients with similar trajectories, we identified distinct 6 month functional recovery trajectories in a large cohort (n = 1046) of adults 18-70 years of age with complicated mild to severe TBI who participated in the Citicoline Brain Injury Treatment Trial (COBRIT). We used multinomial logistic fixed effect models and backward elimination, forward selection, and forward stepwise selection with several stopping rules to explore baseline predictors of functional recovery trajectory. Based on statistical and clinical considerations, the seven-class model was deemed superior. Visualization of these seven functional recovery trajectories revealed that each trajectory class started at one of three recovery levels at 1 month, which, for ease of reference we labeled groups A-C: Group A, good recovery (two classes; A1 and A2); Group B, moderate disability (two classes; B1 and B2); and Group C, severe disability (three classes; C1, C2, and C3). By 6 months, these three groups experienced dramatically divergent trajectories. Group A experienced stable good recovery (A1, n = 115) or dramatic decline (A2, n = 4); Group B experienced rapid complete recovery (B1, n = 71) or gradual recovery (B2, n = 742); Group C experienced dramatic rapid recovery (C1, n = 12), no recovery (C2, n = 91), or death (C3, n = 11). Trajectory class membership was not predicted by citicoline treatment (p = 0.57). The models identified demographic, pre-injury, and injury-related predictors of functional recovery trajectory, including: age, race, education, pre-injury employment, pre-injury diabetes, pre-injury psychiatric disorder, site, Glasgow Coma Scale (GCS) score, post-traumatic amnesia, TBI mechanism, major extracranial injury, hemoglobin, and acute computed tomographic (CT) findings. GCS was the most consistently selected predictor across all models. All models also selected at least one demographic or pre-injury medical predictor. LCMM successfully identified dramatically divergent, clinically meaningful 6 month recovery trajectories with utility to inform clinical trial design.

Project description:Polytrauma and traumatic brain injury (TBI) frequently co-occur and outcomes are routinely measured by the Glasgow Outcome Scale-Extended (GOSE). Polytrauma may confound GOSE measurement of TBI-specific outcomes. Adult patients with TBI from the prospective Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study had presented to a Level 1 trauma center after injury, received head computed tomography (CT) within 24 h, and completed the GOSE at 3 months and 6 months post-injury. Polytrauma was defined as an Abbreviated Injury Score (AIS) ≥3 in any extracranial region. Univariate regressions were performed using known GOSE clinical cutoffs. Multi-variable regressions were performed for the 3- and 6-month GOSE, controlling for known demographic and injury predictors. Of 361 subjects (age 44.9 ± 18.9 years, 69.8% male), 69 (19.1%) suffered polytrauma. By Glasgow Coma Scale (GCS) assessment, 80.1% had mild, 5.8% moderate, and 14.1% severe TBI. On univariate logistic regression, polytrauma was associated with increased odds of moderate disability or worse (GOSE ≤6; 3 month odds ratio [OR] = 2.57 [95% confidence interval (CI): 1.50-4.41; 6 month OR = 1.70 [95% CI: 1.01-2.88]) and death/severe disability (GOSE ≤4; 3 month OR = 3.80 [95% CI: 2.03-7.11]; 6 month OR = 3.33 [95% CI: 1.71-6.46]). Compared with patients with isolated TBI, more polytrauma patients experienced a decline in GOSE from 3 to 6 months (37.7 vs. 24.7%), and fewer improved (11.6 vs. 22.6%). Polytrauma was associated with greater univariate ordinal odds for poorer GOSE (3 month OR = 2.79 [95% CI: 1.73-4.49]; 6 month OR = 1.73 [95% CI: 1.07-2.79]), which was conserved on multi-variable ordinal regression (3 month OR = 3.05 [95% CI: 1.76-5.26]; 6 month OR = 2.04 [95% CI: 1.18-3.42]). Patients with TBI with polytrauma are at greater risk for 3- and 6-month disability compared with those with isolated TBI. Methodological improvements in assessing TBI-specific disability, versus disability attributable to all systemic injuries, will generate better TBI outcomes assessment tools.

Project description:ObjectiveThe two objectives of this study were (1) to replicate the previous finding that a single nucleotide polymorphism (SNP) in the ANKK1 gene (SNP rs1800497 formerly known as the DRD2 TAQ1 A allele) is associated with measures of learning and response latency after traumatic brain injury (TBI) and (2) to further characterize the genetic basis of the effect by testing the strength of association and degree of linkage disequilibrium between the cognitive outcome measures and a selected ensemble of 31 polymorphisms from three adjacent genes in the region of rs1800497.MethodA cohort of 54 patients with TBI and 21 comparison subjects were genotyped for the DRD2 TAQ1 A polymorphism (rs1800497). Ninety-three patients with TBI and 48 comparison subjects (the current cohort and an earlier independent cohort) were also genotyped for 31 additional neighbouring polymorphisms in NCAM, ANKK1 and DRD2. TBI patients were studied 1 month after injury. All subjects completed memory and attention tests, including the California Verbal Learning Test (CVLT) recognition task and the Gordon Continuous Performance Test (CPT).ResultsAs in a previous study the T allele of TAQ1 A (rs1800497) was associated with poorer performance on the CVLT recognition trial in both TBI and control subjects. There was also a significant diagnosis-by-allele interaction on CPT measures of response latency, largely driven by slower performance in the TBI participants with the T allele. Analysis of 31 additional neighbouring polymorphisms from NCAM, ANKK1 and DRD2 in the TBI patients showed four haploblocks. A haploblock of three SNPs in ANKK1 (rs11604671, rs4938016 and rs1800497 (TAQ1A)) showed the greatest association with cognitive outcome measures.ConclusionsThe results confirm a previously published association between the TAQ1 A (rs1800497) T allele and cognitive outcome measures 1 month after TBI and suggest that a haploblock of polymorphisms in ANKK1, rather than the adjacent DRD2 gene, has the highest association with these measures after TBI.

Dataset Information

Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury.

Publications

Association of a common genetic variant within ANKK1 with six-month cognitive performance after traumatic brain injury.

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