Screening for PTSD and TBI in Veterans using Routine Clinical Laboratory Blood Tests.

Post-traumatic stress disorder (PTSD) is a mental disorder diagnosed by clinical interviews, self-report measures and neuropsychological testing. Traumatic brain injury (TBI) can have neuropsychiatric symptoms similar to PTSD. Diagnosing PTSD and TBI is challenging and more so for providers lacking specialized training facing time pressures in primary care and other general medical settings. Diagnosis relies heavily on patient self-report and patients frequently under-report or over-report their symptoms due to stigma or seeking compensation. We aimed to create objective diagnostic screening tests utilizing Clinical Laboratory Improvement Amendments (CLIA) blood tests available in most clinical settings. CLIA blood test results were ascertained in 475 male veterans with and without PTSD and TBI following warzone exposure in Iraq or Afghanistan. Using random forest (RF) methods, four classification models were derived to predict PTSD and TBI status. CLIA features were selected utilizing a stepwise forward variable selection RF procedure. The AUC, accuracy, sensitivity, and specificity were 0.730, 0.706, 0.659, and 0.715, respectively for differentiating PTSD and healthy controls (HC), 0.704, 0.677, 0.671, and 0.681 for TBI vs. HC, 0.739, 0.742, 0.635, and 0.766 for PTSD comorbid with TBI vs HC, and 0.726, 0.723, 0.636, and 0.747 for PTSD vs. TBI. Comorbid alcohol abuse, major depressive disorder, and BMI are not confounders in these RF models. Markers of glucose metabolism and inflammation are among the most significant CLIA features in our models. Routine CLIA blood tests have the potential for discriminating PTSD and TBI cases from healthy controls and from each other. These findings hold promise for the development of accessible and low-cost biomarker tests as screening measures for PTSD and TBI in primary care and specialty settings.

Utilization of machine learning for identifying symptom severity military-related PTSD subtypes and their biological correlates.

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6-10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819-0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.

Gabapentin Enacarbil Extended-Release Versus Placebo: A Likely Responder Reanalysis of a Randomized Clinical Trial.

BACKGROUND: We reanalyzed a multisite 26-week randomized double-blind placebo-controlled clinical trial of 600 mg twice-a-day Gabapentin Enacarbil Extended-Release (GE-XR), a gabapentin prodrug, designed to evaluate safety and efficacy for treating alcohol use disorder. In the original analysis (n = 338), published in 2019, GE-XR did not differ from placebo. Our aim is to advance precision medicine by identifying likely responders to GE-XR from the trial data and to determine for likely responders if GE-XR is causally superior to placebo. METHODS: The primary outcome measure in the reanalysis is the reduction from baseline of the number of heavy drinking days (ΔHDD). Baseline features including measures of alcohol use, anxiety, depression, mood states, sleep, and impulsivity were used in a random forest (RF) model to predict ΔHDD to treatment with GE-XR based on those assigned to GE-XR. The resulting RF model was used to obtain predicted outcomes for those randomized to GE-XR and counterfactually to those randomized to placebo. Likely responders to GE-XR were defined as those predicted to have a reduction of 14 days or more. Tests of causal superiority of GE-XR to placebo were obtained for likely responders and for the whole sample. RESULTS: For likely responders, GE-XR was causally superior to placebo (p < 0.0033), while for the whole sample, there was no difference. Likely responders exhibited improved outcomes for the related outcomes of percent HDD and drinks per week. Compared with unlikely responders, at baseline likely responders had higher HDDs; lower levels of anxiety, depression, and general mood disturbances; and higher levels of cognitive and motor impulsivity. CONCLUSIONS: There are substantial causal benefits of treatment with GE-XR for a subset of patients predicted to be likely responders. The likely responder statistical paradigm is a promising approach for analyzing randomized clinical trials to advance personalized treatment.

Prevalence and Diagnosis Rates of Childhood ADHD Among Racial-Ethnic Groups in a Public Mental Health System.

OBJECTIVE: This study estimated the proportions of Hispanic and non-Hispanic white and black children ages three to 17 with a diagnosis of attention-deficit hyperactivity disorder (ADHD) receiving services from the New York State public mental health system (NYS PMHS) and their annual treated ADHD prevalence rates. Findings were compared with those of recent national studies of general population samples. METHODS: Data were from a 2011 survey of users of NYS PMHS nonresidential services. Adjusted odds ratios compared the probability of an ADHD diagnosis among the groups by age, gender, and insurance type. Prevalence rates were compared among groups by age and gender. RESULTS: An estimated 133,091 children used the NYS PMHS, of whom 31% had an ADHD diagnosis. The prevalence rate of ADHD among whites was significantly lower than that among Hispanics or blacks in all gender and age groups except Hispanic females ages 13 to 17. White children were significantly less likely than black children to receive an ADHD diagnosis. CONCLUSIONS: National studies have reported higher ADHD rates among white children. Compared with children in the NYS PMHS, those in national studies had multiple access points to care, including private psychiatrists and clinicians and primary care practitioners. The higher reported ADHD rates in national studies may reflect higher rates of private insurance among white children, which would increase the likelihood of their using private practitioners. Cultural factors that influence whether and where care is sought and whether practitioners appropriately diagnosis ADHD may also explain the difference in findings.

Access to and use of non-inpatient services in New York State among racial-ethnic groups.

OBJECTIVE Nationwide studies contrasting service use of racial-ethnic groups provide an overview of disparities, but because of variation in populations and service systems, local studies are required to identify specific targets for remedial action. The authors report on the use of non-inpatient services regulated in New York State (NYS) and report use by the state's larger cultural groups. METHODS Data from the NYS Patient Characteristics Survey were used to estimate annual treated prevalence and treatment intensity, defined as the average number of annual weeks in service for non-Hispanic blacks, Hispanics, Asians, and non-Hispanic whites. The latter rates were obtained for specific types of treatment use, by person's age and diagnosis, for the state and for population density-defined regions. Statistical methods contrasted rates of whites with other groups. RESULTS A total of 578,496 individuals in these racial-ethnic groups were served in 2,500 programs, and 51% of those served were nonwhite. Treated prevalence rates of whites were lower than those of blacks and Hispanics and were substantially higher than prevalence rates for Asians. Statewide treatment intensity rates of all racial-ethnic and age groups were comparable except for lower use among Asians >65. Key findings from granular analyses were lower treatment intensity rates for black youths with disruptive disorders, Hispanic adults with anxiety disorders, and Asians >65 with depression compared with white counterparts. In upstate metropolitan areas, black youths and Hispanic adults received services in fewer weeks than whites, and in the New York City metropolitan area, whites >65 had higher treatment intensity rates than contrast groups. CONCLUSIONS Findings suggest a need for assistance to black families in negotiating the multiple systems used by their children, clinical training focusing on cultural symptom presentation, screening of Asians in community settings, and mandated cultural competency assessments for all programs.

Declining use of electroconvulsive therapy in United States general hospitals.

BACKGROUND: Falling duration of psychiatric inpatient stays over the past 2 decades and recent recommendations to tighten federal regulation of electroconvulsive therapy (ECT) devices have focused attention on trends in ECT use, but current national data have been unavailable. METHODS: We calculated the annual number of inpatient stays involving ECT and proportion of general hospitals conducting the procedure at least once in the calendar year with a national sample of discharges from 1993 to 2009. We estimated adjusted probabilities that inpatients with severe recurrent major depression (n = 465,646) were treated in a hospital that conducts ECT and, if so, received the procedure. RESULTS: The annual number of stays involving ECT fell from 12.6 to 7.2/100,000 adult US residents, driven by dramatic declines among elderly persons, whereas the percentage of hospitals conducting ECT decreased from 14.8% to 10.6%. The percentage of stays for severe recurrent major depression in hospitals that conducted ECT fell from 70.5% to 44.7%, whereas receipt of ECT where conducted declined from 12.9% to 10.5%. For depressed inpatients, the adjusted probability that the treating hospital conducts ECT fell 34%, whereas probability of receiving ECT was unchanged for patients treated in facilities that conducted the procedure. Adjusted declines were greatest for elderly persons. Throughout the period inpatients from poorer neighborhoods or who were publicly insured or uninsured were less likely to receive care from hospitals conducting ECT. CONCLUSIONS: Electroconvulsive therapy use for severely depressed inpatients has fallen markedly, driven exclusively by a decline in the probability that their hospital conducts ECT.

Racial differences in the availability and use of electroconvulsive therapy for recurrent major depression.

BACKGROUND: Black Americans with depression were less likely to receive electroconvulsive therapy (ECT) than whites during the 1970s and 80s. This pattern was commonly attributed to treatment of blacks in lower quality hospitals where ECT was unavailable. We investigated whether a racial difference in receiving ECT persists, and, if so, whether it arises from lesser ECT availability or from lesser ECT use within hospitals conducting the procedure. METHODS: Black or white inpatient stays for recurrent major depression from 1993 to 2007 (N=419,686) were drawn from an annual sample of US community hospital discharges. The marginal disparity ratio estimated adjusted racial differences in the probabilities of (1) admission to a hospital capable of conducting ECT (availability), and (2) ECT utilization if treated where ECT is conducted (use). RESULTS: Across all hospitals, the probability of receiving ECT for depressed white inpatients (7.0%) greatly exceeded that for blacks (2.0%). Probability of ECT availability was slightly greater for whites than blacks (62.0% versus 57.8%), while probability of use was markedly greater (11.8% versus 3.9%). The white versus black marginal disparity ratio for ECT availability was 1.07 (95% confidence interval 1.06-1.07) and stable over the period, while the ratio for use fell from 3.2 (3.1-3.4) to 2.5 (2.4-2.7). LIMITATIONS: Depressed persons treated in outpatient settings or receive no care are excluded from analyses. CONCLUSIONS: Depressed black inpatients continue to be far less likely than whites to receive ECT. The difference arises almost entirely from lesser use of ECT within hospitals where it is available.

Length of stay of pediatric mental health emergency department visits in the United States.

OBJECTIVE: To compare pediatric mental health emergency department visits to other pediatric emergency department visits, focusing on length of stay. METHOD: We analyzed data from the National Hospital Ambulatory Medical Care Survey, a nationally representative sample of US emergency department visits from 2001 to 2008, for patients aged ≤18 years (n = 73,015). Visits with a principal diagnosis of a mental disorder (n = 1,476) were compared to visits (n = 71,539) with regard to patient and hospital characteristics, treatment, and length of stay. Predictors of prolonged mental health visits were identified. RESULTS: Mental health visits were more likely than other visits to arrive by ambulance (21.8% versus 6.3%, p < .001), to be triaged to rapid evaluation (27.9% versus 14.9%, p < .001), and to be admitted (16.4% versus 7.6%, p < .001) or transferred (15.7% versus 1.5%, p < .001). The median length of stay for mental health visits (169 minutes) significantly exceeded that of other visits (108 minutes). The odds of extended stay beyond 4 hours for mental health visits was almost twice that for other visits (adjusted odds ratio 1.9, 95% CI = 1.5-2.4) and was not explained by observed differences in evaluation, treatment, or disposition. Among mental health visits, advancing calendar year of study, intentional self-injury, age 6-13 years, Northeastern, Southern, and metropolitan hospital location, use of laboratory studies, and patient transfer all predicted extended stays. CONCLUSIONS: Compared with other pediatric emergency visits, mental health visits are longer, are more frequently triaged to urgent evaluation, and more likely to result in patient admission or transfer, thereby placing distinctive burdens on US emergency departments.

The Nathan Kline Institute cultural competency assessment scale: psychometrics and implications for disparity reduction.

The NKI Cultural Competency Assessment Scale measures organizational CC in mental health outpatient settings. We describe its development and results of tests of its psychometric properties. When tested in 27 public mental health settings, factor analysis discerned three factors explaining 65% of the variance; each factor related to a stage of implementation of CC. Construct validity and inter-rater reliability were satisfactory. In tests of predictive validity, higher scores on items related to linguistic and service accommodations predicted a reduction in service disparities for engagement and retention outcomes for Hispanics. Disparities for Blacks essentially persisted independent of CC scores.

Estimating treated prevalence and service utilization rates: assessing disparities in mental health.

There is considerable public concern about health disparities among different cultural/racial/ethnic groups. Important process measures that might reflect inequities are treated prevalence and the service utilization rate in a defined period of time. We have previously described a method for estimating N, the distinct number who received service in a year, from a survey of service users at a single point in time. The estimator is based on the random variable 'time since last service', which enables the estimation of treated prevalence. We show that this same data can be used to estimate the service utilization rate, E(J), the mean number of services in the year. If the sample is typical with respect to the time since last visit, the MLE of E(J) is asymptotically unbiased. Confidence intervals and a global test of equality of treated prevalence and service utilization rates among several groups are given. A data set of outpatient mental health services from a county in New York State for which the true values of the parameters are known is analyzed as an illustration of the methods and an appraisal of their accuracy.

Assessing onset of treatment benefit in depression and anxiety: conceptual considerations.

OBJECTIVE: Methods for characterizing the onset of treatment benefit in major depressive disorder and generalized anxiety disorder have been studied for some time, yet there is no universal agreement as to the best approaches. Our purpose is to summarize the conceptual framework underlying modern methods for characterizing onset and detailed approaches for which there is consensus from the perspective of a clinician, clinical researcher, and statistician. Possible alternatives to unresolved issues are discussed. PARTICIPANTS: There were 17 experts from academia, the pharmaceutical industry, and the US Food and Drug Administration who met on April 19, 2007, to consider the issues. Many others from sponsoring firms observed the proceedings. EVIDENCE: A series of papers was presented at a consensus meeting and, after discussions, a sense of the participants was obtained. A small group subsequently reviewed the material and articles from the literature and prepared this article, which was reviewed by all of the participants. CONCLUSIONS: The elements that form the basis for describing onset of treatment benefit include defining a clinical event or measurable threshold that validly signals that a treatment has begun to provide clinically meaningful and sustained improvement and utilizing methods for estimating the probability of crossing the onset threshold, the distribution of time to onset for those who do cross, and when to alter or change interventions if the treatment is unsuccessful.

Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees.

OBJECTIVE: Cocaine dependence is associated with severe medical, psychiatric, and social morbidity, but no pharmacotherapy is approved for its treatment in the United States. The atypical antiepileptic vigabatrin (gamma-vinyl gamma-aminobutyric acid [GABA]) has shown promise in animal studies and open-label trials. The purpose of the present study was to assess the efficacy of vigabatrin for short-term cocaine abstinence in cocaine-dependent individuals. METHOD: Participants were treatment seeking parolees who were actively using cocaine and had a history of cocaine dependence. Subjects were randomly assigned to a fixed titration of vigabatrin (N=50) or placebo (N=53) in a 9-week double-blind trial and 4-week follow-up assessment. Cocaine use was determined by directly observed urine toxicology testing twice weekly. The primary endpoint was full abstinence for the last 3 weeks of the trial. RESULTS: Full end-of-trial abstinence was achieved in 14 vigabatrin-treated subjects (28.0%) versus four subjects in the placebo arm (7.5%). Twelve subjects in the vigabatrin group and two subjects in the placebo group maintained abstinence through the follow-up period. The retention rate was 62.0% in the vigabatrin arm versus 41.5% in the placebo arm. Among subjects who reported prestudy alcohol use, vigabatrin, relative to placebo, was associated with superior self-reported full end-of-trial abstinence from alcohol (43.5% versus 6.3%). There were no differences between the two groups in drug craving, depressed mood, anxiety, or Clinical Global Impression scores, and no group differences in adverse effects emerged. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial supports the safety and efficacy of short-term vigabatrin treatment of cocaine dependence.

Model-based multiplicity estimation of population size.

A survey is conducted at w of K selection units or lists, e.g. health care institutions or weeks in a year, to estimate N, the total number of individuals with particular characteristics. Our estimator utilizes two items determined for each survey participant: the number, u, among the w lists in S and the number, j, among all K lists on which each survey participant appears. In its traditional form, selection units are chosen using probability sampling and the statistical properties of the estimator derive from the sampling mechanism. Here, selection units are purposively chosen to maximize the chance that they are 'typical' and a model-based analysis is used for inference. If the sample is typical, the ML estimators of N and E(J) are unbiased. If a condition on the second moment of U/J is satisfied, the model-based variance of the estimator of N based on a purposively chosen typical sample is smaller than one based on a randomly chosen sample. Methods to test whether the typical assumption is valid using data from the survey are not yet available. The importance of proper selection of the sample to maximize the chance that it is typical and model breakdown does not occur must be emphasized.

Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction.

This study examined the safety and efficacy of gamma vinyl-GABA (GVG, vigabatrin) for the treatment of methamphetamine and/or cocaine addiction. A total of 30 subjects, who met DSM-IV criteria for methamphetamine and/or cocaine dependence, were enrolled in an open label 9-week safety study. The protocol was specifically designed to include extensive visual field monitoring as well as outcome measures of therapeutic efficacy. Patients were screened twice weekly for the presence of urinary cocaine, methamphetamine, heroin, alcohol, and marijuana. In total, 18/30 subjects completed the study and 16/18 tested negative for methamphetamine and cocaine during the last 6 weeks of the trial. GVG did not produce any visual field defects or alterations in visual acuity. Furthermore, it did not produce changes in vital signs even with continued use of methamphetamine and cocaine. Thus, under conditions that appear to be appropriate for the successful treatment of methamphetamine and/or cocaine addiction, GVG is safe.

Estimating population size and duplication rates when records cannot be linked.

The capture-recapture approach to estimating the size of a population is a well-studied area of statistics. The number of distinct individuals, N(A) and N(B), on each of two lists, A and B, and the number common to both lists, N(AB), are used to form an estimate of the binomial probability of being on one of the lists, which then allows an estimate to be made of the size of the population. Critical to the method is an accurate count of N(AB). We consider situations in which this count is not available. Such problems arise in a variety of behavioural health contexts in which the need for protection of privacy may prevent sharing identifying information, so it is not possible to specifically match an individual who appears on one list with an individual on the other. Suppose that the birth dates and/or other demographics of individuals on each list are known. We introduce two methods for estimating the duplication rates and the size of the population. Conditioning on the set beta of birth dates of those on list B, N(A) and N(B), the maximum likelihood estimators (MLEs) and their variance are derived. The MLEs are based on the proportion of individuals on list A whose birth dates fall in beta. This approach is particularly useful if list B itself contains duplicates. The second model utilizes the full sample distribution of the birth dates. We generalize this approach to accommodate multiple demographic characteristics. The approaches are applied to the problem of estimating duplication rates and the population size of veterans who have mental illness in Kings County, NY. The data are lists of those receiving service from the Veterans Administration system and from providers funded or certified by the New York State Office of Mental Health.

National Depressive and Manic-Depressive Association consensus statement on the use of placebo in clinical trials of mood disorders.

A consensus conference on the use of placebo in mood disorder studies consisted of expert presentations on bioethics, biostatistics, unipolar depression, and bipolar disorder. Work groups considered evidence and presented statements to the group. Although it was not possible to write a document for which there was complete agreement on all issues, the final document incorporated input from all authors. There was consensus that placebo has a definite role in mood disorder studies. Findings of equivalence between a new drug and standard treatment in active control studies is not evidence of efficacy unless the new drug is also significantly more effective than placebo. Add-on studies in which patients are randomized to standard therapy plus the investigational drug or standard therapy plus placebo are especially indicated for high-risk patients. Mood disorders in elderly and pediatric patients are understudied, and properly designed trials are urgently needed. Research is needed on the ethical conduct of studies to limit risks of medication-free intervals and facilitate poststudy treatment. Patients must fully understand the risks and lack of individualized treatment involved in research.

Statistical determination of cost-effectiveness frontier based on net health benefits.

Statistical methods are given for producing a cost-effectiveness frontier for an arbitrary number of programs. In the deterministic case, the net health benefit (NHB) decision rule is optimal; the rule funds the program with the largest positive NHB at each lambda, the amount a decision-maker is willing to pay for an additional unit of effectiveness. For bivariate normally distributed cost and effectiveness variables and a specified lambda, a statistical procedure is presented, based on the method of constrained multiple comparisons with the best (CMCB), for determining the program with the largest NHB. A one-tailed t test is used to determine if the NHB is positive. To obtain a statistical frontier in the lambda-NHB plane, we develop a method to produce the region in which each program has the largest NHB, by pivoting a CMCB confidence interval. A one-sided version of Fieller's theorem is used to determine the region where the NHB of each program is positive. At each lambda, the pointwise error rate is bounded by a prespecified alpha. Upper bounds on the familywise error rate, the probability of an error at any value of lambda, are given. The methods are applied to a hypothetical clinical trial of antipsychotic agents.

The familywise error rate of a simultaneous confidence band for the incremental net health benefit.

Interest in the use of net health benefit in cost-effectiveness analysis derives from its optimality property for decision-making. A description of the results of an economic evaluation of health care interventions is incomplete if it does not include point and interval estimates of this outcome measure. A simultaneous confidence band for the incremental net health benefit, INHB(lambda), for all lambda may be obtained by forming a confidence interval based on student's t statistic, and letting the willingness-to-pay value, lambda, run over all values. The familywise error rate (FWER) of the simultaneous confidence band is the probability that the confidence interval does not cover the true INHB(lambda) for some value of lambda. We show that the FWER equals P(T(2)>t(2)), where T(2) follows Hotelling's central distribution and that the simultaneous confidence band does not cover the true INHB(lambda) if and only if a T(2) based confidence ellipsoid does not cover the true mean c-e vector.