Jeremy J. Davis

Identification of blood biomarkers for psychosis using convergent functional genomics.

There are to date no objective clinical laboratory blood tests for psychotic disease states. We provide proof of principle for a convergent functional genomics (CFG) approach to help identify and prioritize blood biomarkers for two key psychotic symptoms, one sensory (hallucinations) and one cognitive (delusions). We used gene expression profiling in whole blood samples from patients with schizophrenia and related disorders, with phenotypic information collected at the time of blood draw, then cross-matched the data with other human and animal model lines of evidence. Topping our list of candidate blood biomarkers for hallucinations, we have four genes decreased in expression in high hallucinations states (Fn1, Rhobtb3, Aldh1l1, Mpp3), and three genes increased in high hallucinations states (Arhgef9, Phlda1, S100a6). All of these genes have prior evidence of differential expression in schizophrenia patients. At the top of our list of candidate blood biomarkers for delusions, we have 15 genes decreased in expression in high delusions states (such as Drd2, Apoe, Scamp1, Fn1, Idh1, Aldh1l1), and 16 genes increased in high delusions states (such as Nrg1, Egr1, Pvalb, Dctn1, Nmt1, Tob2). Twenty-five of these genes have prior evidence of differential expression in schizophrenia patients. Predictive scores, based on panels of top candidate biomarkers, show good sensitivity and negative predictive value for detecting high psychosis states in the original cohort as well as in three additional cohorts. These results have implications for the development of objective laboratory tests to measure illness severity and response to treatment in devastating disorders such as schizophrenia.

Utility of the Response Bias Scale (RBS) and other MMPI-2 validity scales in predicting TOMM performance

The present study represents a replication and extension of the original Response Bias Scale (RBS) validation study. In addition to examining the relationship between the Test of Memory Malingering (TOMM), RBS, and several other well-researched Minnesota Multiphasic Personality Inventory 2 (MMPI-2) validity scales (i.e., F, Fb, Fp, and the Fake Bad Scale), the present study also included the recently developed Infrequency Post-Traumatic Stress Disorder Scale and the Henry-Heilbronner Index (HHI) of the MMPI-2. Findings from this retrospective data analysis (N=46) demonstrated the superiority of the RBS, and to a certain extent the HHI, over other MMPI-2 validity scales in predicting TOMM failure within the outpatient Veterans Affairs population. Results of the current study confirm the clinical utility of the RBS and suggest that, particularly if the MMPI-2 is an existing part of the neuropsychological assessment, examination of RBS scores is an efficient means of detecting negative response bias.

Treatment adherence in cognitive processing therapy for combat-related PTSD with history of mild TBI.

OBJECTIVE This retrospective study examined treatment adherence in Cognitive Processing Therapy (CPT) for combat-related posttraumatic stress disorder (PTSD) in Veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) with and without history of mild traumatic brain injury (mTBI). METHOD Medical record review of consecutive referrals to an outpatient PTSD clinic identified veterans diagnosed with combat-related PTSD who began treatment with CPT. The sample (N = 136) was grouped according to positive (n = 44) and negative (n = 92) mTBI history. Groups were compared in terms of presenting symptoms and treatment adherence. RESULTS The groups were not different on a pretreatment measure of depression, but self-reported and clinician-rated PTSD symptoms were higher in veterans with history of mTBI. The treatment completion rate was greater than 61% in both groups. The number of sessions attended averaged 9.6 for the PTSD group and 7.9 for the mTBI/PTSD group (p = .05). IMPLICATIONS Given the lack of marked group differences in treatment adherence, these initial findings suggest that standard CPT for PTSD may be a tolerable treatment for OEF/OIF veterans with a history of PTSD and mTBI as well as veterans with PTSD alone.

Examination of performance validity test failure in relation to number of tests administered.

This study examined the relationship among performance validity test (PVT) failure, number of PVTs administered, and participant characteristics including demographic, diagnostic, functional, and contextual factors in a clinical sample (N = 158) of outpatient physiatry referrals. The number of PVTs failed and the number administered showed a small non-significant correlation (rs = .13, p = .10). Participant characteristics showed associations with PVT failure consistent with prior research. A negative binomial regression model was fitted using number of PVTs failed as outcome and age, education, number of PVTs administered, clinical versus medico-legal context, and functional status as predictors. Although education and functional status were significant predictors of number of PVTs failed, the number of PVTs administered was not. A second analytic approach focused on observed false positive rates in a neurologic no-incentive (NNI) sample subset (n = 87). In contrast to a recent proposal based on statistical simulation, observed false positive rates were lower than predicted rates in NNI participants administered six, seven, or eight PVTs using a two-PVT failure cutoff. These results are interpreted as mitigating concerns that increased PVT failure is necessarily the outcome of increased PVT administration.

Finger Tapping Test Performance as a Measure of Performance Validity

The Finger Tapping Test (FTT) has been presented as an embedded measure of performance validity in most standard neuropsychological evaluations. The present study evaluated the utility of three different scoring systems intended to detect invalid performance based on FTT. The scoring systems were evaluated in neuropsychology cases from clinical and independent practices, in which credible performance was determined based on passing all performance validity measures or failing two or more validity indices. Each FTT scoring method presented with specificity rates at approximately 90% and sensitivity of slightly more than 40%. When suboptimal performance was based on the failure of any of the three scoring methods, specificity was unchanged and sensitivity improved to 50%. The results are discussed in terms of the utility of combining multiple scoring measures for the same test as well as benefits of embedded measures administered over the duration of the evaluation.

Performance Validity and Neuropsychological Outcomes in Litigants and Disability Claimants

This study examined the relationship of performance validity and neuropsychological outcomes in a sample of individuals referred for independent neuropsychological examination in the context of reported traumatic brain injury (82% mild). Archival data were examined on 175 participants aged 20 to 65 who were administered at least two performance validity measures. Participants who passed all effort measures (Pass; n = 61) outperformed those who failed two or more (Fail; n = 70) on the majority of tests in the neuropsychological battery. The Fail group showed a higher percentage of impaired test scores than the Pass group with impairment defined at three levels (T scores < 40, 35, and 30). At the most conservative impairment cutoff (T < 30), 16% of the Pass group demonstrated impaired scores on more than three measures, while 79% of the Fail group showed impaired scores on more than three measures. The number of effort measures failed correlated highly with the overall test battery mean (r = −.73). On cognitive domain summary scores, effect sizes based on levels of effort (d = 1.12 to 1.86) were higher than those based on injury severity (d = 0.03 to 0.36).

Derivation of an Embedded Rey Auditory Verbal Learning Test Performance Validity Indicator

This study derived an embedded performance validity indicator for the Rey Auditory Verbal Learning Test (AVLT) using an archival dataset. Participants aged 20 to 65 (N = 167) who reported traumatic brain injury and completed at least two performance validity tests were included. The group who passed all performance validity measures (n = 68) demonstrated higher scores on all AVLT trials than the group who failed two or more validity indicators (n = 62). Bayesian model averaging was used to identify the optimal combination of AVLT variables for group discrimination; Total Learning and Recognition raw scores were selected. Logistic regression using these variables showed excellent discrimination with an area under the curve of. 85. The resulting AVLT performance validity index demonstrated sensitivity of. 55 with specificity of. 91. Further study of this index is warranted and cross-validation is recommended prior to clinical use.

Digit Span Age Scaled Score in Middle-Aged Military Veterans: Is It More Closely Associated with TOMM Failure than Reliable Digit Span?

The relative usefulness of two digit span (DS) variables in detecting negative response bias, as defined by below cut-off performance on the Test of Memory Malingering (TOMM), was examined among primarily middle-aged military veteran outpatients who were judged clinically to be at increased risk for displaying negative response bias on cognitive testing. Digit span variables included DS Age Scaled Score (DS Age SS) and Reliable DS. Findings from this retrospective data analysis (N = 46) suggest that DS Age SS is preferable for use over Reliable DS in predicting TOMM failure. Results of the current study suggest that, particularly if the Wechsler scales are an existing part of the neuropsychological assessment, examination of DS Age SS is an efficient means of detecting negative response bias.

Further consideration of Advanced Clinical Solutions Word Choice: comparison to the Recognition Memory Test-words and classification accuracy in a clinical sample.

Word Choice (WC), a test in the Advanced Clinical Solutions package for Wechsler measures, was examined in two studies. The first study compared WC to the Recognition Memory Test-Words (RMT-W) in a clinical sample (N = 46). WC scores were significantly higher than RMT-W scores overall and in sample subsets grouped by separate validity indicators. In item-level analyses, WC items demonstrated lower frequency, greater imageability, and higher concreteness than RMT-W items. The second study explored WC classification accuracy in a different clinical sample grouped by separate validity indicators into Pass (n = 54), Fail-1 (n = 17), and Fail-2 (n = 8) groups. WC scores were significantly higher in the Pass group (M = 49.1, SD = 1.9) than in the Fail-1 (M = 46.0, SD = 5.3) and Fail-2 (M = 44.1, SD = 4.8) groups. WC demonstrated area under the curve of .81 in classifying Pass and Fail-2 participants. Using the test manual cutoff associated with a 10% false positive rate, sensitivity was 38% and specificity was 96% in Pass and Fail-2 groups with 24% of Fail-1 participants scoring below cutoff. WC may be optimally used in combination with other measures given observed sensitivity.

Reply to Commentary by Bilder, Sugar, and Helleman (2014 this issue) on Minimizing False Positive Error With Multiple Performance Validity Tests

Bilder, Sugar, and Helleman (2014 this issue) have criticized recent publications on performance validity test (PVT) failure in clinical samples. Bilder and colleagues appear to make an idiosyncratic interpretation of recent research and inconsistently apply principles of null hypothesis significance testing. Overall, their position seems to propose that PVTs should be held to a higher psychometric standard than conventional neuropsychological tests. Problematic aspects of these criticisms are discussed. Additional consideration is given to research aims and findings.