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Item Comparison of Common Outcome Measures for Assessing Independence in Patients Diagnosed with Disorders of Consciousness: A Traumatic Brain Injury Model Systems Study(Mary Ann Liebert, 2022) Snider, Samuel B.; Kowalski, Robert G.; Hammond, Flora M.; Izzy, Saef; Shih, Shirley L.; Rovito, Craig; Edlow, Brian L.; Zafonte, Ross D.; Giacino, Joseph T.; Bodien, Yelena G.; Physical Medicine and Rehabilitation, School of MedicinePatients with disorders of consciousness (DoC) after traumatic brain injury (TBI) recover to varying degrees of functional dependency. Dependency is difficult to measure but critical for interpreting clinical trial outcomes and prognostic counseling. In participants with DoC (i.e., not following commands) enrolled in the TBI Model Systems National Database (TBIMS NDB), we used the Functional Independence Measure (FIM®) as the reference to evaluate how accurately the Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) assess dependency. Using the established FIM-dependency cut-point of <80, we measured the classification performance of literature-derived GOSE and DRS cut-points at 1-year post-injury. We compared the area under the receiver operating characteristic curve (AUROC) between the DRSDepend, a DRS-derived marker of dependency, and the data-derived optimal GOSE and DRS cut-points. Of 18,486 TBIMS participants, 1483 met inclusion criteria (mean [standard deviation (SD)] age = 38 [18] years; 76% male). The sensitivity of GOSE cut-points of ≤3 and ≤4 (Lower Severe and Upper Severe Disability, respectively) for identifying FIM-dependency were 97% and 98%, but specificities were 73% and 51%, respectively. The sensitivity of the DRS cut-point of ≥12 (Severe Disability) for identifying FIM-dependency was 60%, but specificity was 100%. The DRSDepend had a sensitivity of 83% and a specificity of 94% for classifying FIM-dependency, with a greater AUROC than the data-derived optimal GOSE (≤3, p = 0.01) and DRS (≥10, p = 0.008) cut-points. Commonly used GOSE and DRS cut-points have limited specificity or sensitivity for identifying functional dependency. The DRSDepend identifies FIM-dependency more accurately than the GOSE and DRS cut-points, but requires further validation.Item COMT Val 158 Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury(Elsevier, 2017-01) Winkler, Ethan A.; Yue, John K.; Ferguson, Adam R.; Temkin, Nancy R.; Stein, Murray B.; Barber, Jason; Yuh, Esther L.; Sharma, Sourabh; Satris, Gabriela G.; McAllister, Thomas W.; Rosand, Jonathan; Sorani, Marco D.; Lingsma, Hester F.; Tarapore, Phiroz E.; Burchard, Esteban G.; Hu, Donglei; Eng, Celeste; Wang, Kevin K.W.; Mukherjee, Pratik; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.; TRACK-TBI Investigators; Psychiatry, School of MedicineMild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings.Item COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury(Springer, 2016-01) Winker, Ethan A.; Yue, John K.; McAllister, Thomas W.; Temkin, Nancy R.; Oh, Sam S.; Burchard, Esteban G.; Hu, Donglei; Ferguson, Adam R.; Lingsma, Hester F.; Burke, John F.; Sorani, Marco D.; Rosand, Jonathan; Yuh, Esther L.; Barber, Jason; Tarapore, Phiroz E.; Gardner, Raquel C.; Sharma, Sourabh; Satris, Gabriela G.; Eng, Celeste; Puccio, Ava M.; Wang, Kevin K.W.; Mukherjee, Pratik; Valadka, Alex B.; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.; Department of Psychiatry, IU School of MedicineMild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551.Item DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury(Springer, 2017-01) Yue, John K.; Winkler, Ethan A.; Rick, Jonathan W.; Burke, John F.; McAllister, Thomas W.; Oh, Sam S.; Burchard, Esteban G.; Hu, Donglei; Rosand, Jonathan; Temkin, Nancy R.; Korley, Frederick K.; Sorani, Marco D.; Ferguson, Adam R.; Lingsma, Hester F.; Sharma, Sourabh; Robinson, Caitlin K.; Yuh, Esther L.; Tarapore, Phiroz E.; Wang, Kevin K.W.; Puccio, Ava M.; Mukherjee, Pratik; Diaz-Arrastia, Ramon; Gordon, Wayne A.; Valadka, Alex B.; Okonkwo, David O.; Manley, Geoffrey T.; TRACK-TBI Investigators; Psychiatry, School of MedicineTraumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI-California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1-5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.Item Measures of outcome for stimulant trials: ACTTION recommendations and research agenda(Elsevier, 2016-01-01) Kiluk, Brian D.; Carroll, Kathleen M.; Duhig, Amy; Falk, Daniel E.; Kampman, Kyle; Lai, Shengan; Litten, Raye Z.; McCann, David J.; Montoya, Ivan D.; Preston, Kenzie L.; Skolnick, Phil; Weisner, Constance; Woody, George; Chandler, Redonna; Detke, Michael J.; Dunn, Kelly; Dworkin, Robert H.; Fertig, Joanne; Gewandter, Jennifer; Moeller, F. Gerard; Ramey, Tatiana; Ryan, Megan; Silverman, Kenneth; Strain, Eric C.; Department of Psychiatry, IU School of MedicineBACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.Item Parkinson's Progression Markers Initiative: A Milestone-Based Strategy to Monitor Parkinson's Disease Progression(IOS Press, 2023) Brumm, Michael C.; Siderowf, Andrew; Simuni, Tanya; Burghardt, Elliot; Choi, Seung Ho; Caspell-Garcia, Chelsea; Chahine, Lana M.; Mollenhauer, Brit; Foroud, Tatiana; Galasko, Douglas; Merchant, Kalpana; Arnedo, Vanessa; Hutten, Samantha J.; O’Grady, Alyssa N.; Poston, Kathleen L.; Tanner, Caroline M.; Weintraub, Daniel; Kieburtz, Karl; Marek, Kenneth; Coffey, Christopher S.; Parkinson’s Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineBackground: Identifying a meaningful progression metric for Parkinson's disease (PD) that reflects heterogeneity remains a challenge. Objective: To assess the frequency and baseline predictors of progression to clinically relevant motor and non-motor PD milestones. Methods: Using data from the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort, we monitored 25 milestones across six domains ("walking and balance"; "motor complications"; "cognition"; "autonomic dysfunction"; "functional dependence"; "activities of daily living"). Milestones were intended to be severe enough to reflect meaningful disability. We assessed the proportion of participants reaching any milestone; evaluated which occurred most frequently; and conducted a time-to-first-event analysis exploring whether baseline characteristics were associated with progression. Results: Half of participants reached at least one milestone within five years. Milestones within the cognitive, functional dependence, and autonomic dysfunction domains were reached most often. Among participants who reached a milestone at an annual follow-up visit and remained active in the study, 82% continued to meet criteria for any milestone at one or more subsequent annual visits and 55% did so at the next annual visit. In multivariable analysis, baseline features predicting faster time to reaching a milestone included age (p < 0.0001), greater MDS-UPDRS total scores (p < 0.0001), higher GDS-15 depression scores (p = 0.0341), lower dopamine transporter binding (p = 0.0043), and lower CSF total α-synuclein levels (p = 0.0030). Symptomatic treatment was not significantly associated with reaching a milestone (p = 0.1639). Conclusion: Clinically relevant milestones occur frequently, even in early PD. Milestones were significantly associated with baseline clinical and biological markers, but not with symptomatic treatment. Further studies are necessary to validate these results, further assess the stability of milestones, and explore translating them into an outcome measure suitable for observational and therapeutic studies.Item Post-Inpatient Brain Injury Rehabilitation Outcomes: Report from the National OutcomeInfo Database(Mary Ann Liebert, Inc., 2016-07-15) Malec, James F.; Kean, Jacob; Physical Medicine and Rehabilitation, School of MedicineThis study examined outcomes for intensive residential and outpatient/community-based post-inpatient brain injury rehabilitation (PBIR) programs compared with supported living programs. The goal of supported living programs was stable functioning (no change). Data were obtained for a large cohort of adults with acquired brain injury (ABI) from the OutcomeInfo national database, a web-based database system developed through National Institutes of Health (NIH) Small Business Technology Transfer (STTR) funding for monitoring progress and outcomes in PBIR programs primarily with the Mayo-Portland Adaptability Inventory (MPAI-4). Rasch-derived MPAI-4 measures for cases from 2008 to 2014 from 9 provider organizations offering programs in 23 facilities throughout the United States were examined. Controlling for age at injury, time in program, and time since injury on admission (chronicity), both intensive residential (n = 205) and outpatient/community-based (n = 2781) programs resulted in significant (approximately 1 standard deviation [SD]) functional improvement on the MPAI-4 Total Score compared with supported living (n = 101) programs (F = 18.184, p < 0.001). Intensive outpatient/community-based programs showed greater improvements on MPAI-4 Ability (F = 14.135, p < 0.001), Adjustment (F = 12.939, p < 0.001), and Participation (F = 16.679, p < 0.001) indices than supported living programs; whereas, intensive residential programs showed improvement primarily in Adjustment and Participation. Age at injury and time in program had small effects on outcome; the effect of chronicity was small to moderate. Examination of more chronic cases (>1 year post-injury) showed significant, but smaller (approximately 0.5 SD) change on the MPAI-4 relative to supported living programs (F = 17.562, p < 0.001). Results indicate that intensive residential and outpatient/community-based PIBR programs result in substantial positive functional changes moderated by chronicity.