Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Cost-effectiveness of brentuximab vedotin in advanced stage Hodgkin's lymphoma: a probabilistic analysis.

BACKGROUND: Treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is a well-established therapy for advanced Hodgkin's lymphoma (HL). However, the recently completed ECHELON-1 trial showed potential net clinical benefit for brentuximab vedotin (BREN+AVD) compared to ABVD as frontline therapy in patients with advanced Hodgkin's lymphoma. The objective of this analysis is to determine whether, on current evidence, BREN+AVD is cost-effective relative to ABVD as frontline therapy in patients with advanced HL. METHODS: We constructed a probabilistic Markov model with two arms and six mutually exclusive health states, using six-month cycle lengths, and a 15-year time horizon. Time-dependent transition probabilities were calculated from 'real-world' data collected by the BC Cancer's Centre for Lymphoid Cancer database or from the literature for ABVD. Time-dependent transition probabilities for BREN+AVD were taken from the ECHELON-1 trial. We estimated the incremental cost and effects per patient of each therapy and calculated the incremental cost-effectiveness ratio (ICER). Costs were measured in 2018 Canadian dollars and effects measured in quality-adjusted life years (QALYs). A probabilistic analysis was used to generate a cost-effectiveness acceptability curve (CEAC). RESULTS: The incremental cost between standard therapy with ABVD and therapy with BREN+AVD was estimated to be $192,336. The regimen of BREN+AVD resulted in a small benefit in terms of QALYs (0.46 QALYs). The estimated ICER was $418,122 per QALY gained. The probabilistic analysis suggests very few (8%) simulations fall below $100,000 per QALY. Even at a threshold of $200,000 per QALY gained, there was only a 24% chance that BREN+AVD would be considered cost-effective. Sensitivity analyses evaluating price reductions for brentuximab showed that these reductions needed to be in excess of 70% for this regimen to be cost-effective at a threshold of $100,000 per QALY. CONCLUSIONS: There may be a clinical benefit associated with BREN+AVD, but on current evidence the benefit is not adequately substantive compared to ABVD therapy given the cost of brentuximab vedotin. Agencies responsible for making decisions about BREN+AVD as frontline therapy for patients with advanced HL should consider whether they are willing to implement this treatment given the current uncertainty and cost-benefit profile, or negotiate substantial price-reductions from the manufacturer should they choose to reimburse.

A time-and-motion approach to micro-costing of high-throughput genomic assays.

BACKGROUND: Genomic technologies are increasingly used to guide clinical decision-making in cancer control. Economic evidence about the cost-effectiveness of genomic technologies is limited, in part because of a lack of published comprehensive cost estimates. In the present micro-costing study, we used a time-and-motion approach to derive cost estimates for 3 genomic assays and processes-digital gene expression profiling (gep), fluorescence in situ hybridization (fish), and targeted capture sequencing, including bioinformatics analysis-in the context of lymphoma patient management. METHODS: The setting for the study was the Department of Lymphoid Cancer Research laboratory at the BC Cancer Agency in Vancouver, British Columbia. Mean per-case hands-on time and resource measurements were determined from a series of direct observations of each assay. Per-case cost estimates were calculated using a bottom-up costing approach, with labour, capital and equipment, supplies and reagents, and overhead costs included. RESULTS: The most labour-intensive assay was found to be fish at 258.2 minutes per case, followed by targeted capture sequencing (124.1 minutes per case) and digital gep (14.9 minutes per case). Based on a historical case throughput of 180 cases annually, the mean per-case cost (2014 Canadian dollars) was estimated to be $1,029.16 for targeted capture sequencing and bioinformatics analysis, $596.60 for fish, and $898.35 for digital gep with an 807-gene code set. CONCLUSIONS: With the growing emphasis on personalized approaches to cancer management, the need for economic evaluations of high-throughput genomic assays is increasing. Through economic modelling and budget-impact analyses, the cost estimates presented here can be used to inform priority-setting decisions about the implementation of such assays in clinical practice.

Valuing the benefit of diagnostic testing for genetic causes of idiopathic developmental disability: willingness to pay from families of affected children.

Idiopathic developmental disability (DD) has been found to put significant psychological distress on families of children with DD. The cause of the disability, however, is unknown for up to one-half of the affected children. Chromosomal abnormalities identified by cytogenetic analysis are the most frequently recognized cause of DD, although they account for less than 10% of cases. Array genomic hybridization (AGH) is a new diagnostic tool that provides a much higher detection rate for chromosomal imbalance than conventional cytogenetic analysis. This increase in diagnostic capability comes at greater monetary costs, which provides an impetus for understanding how individuals value genetic testing for DD. This study estimated the willingness to pay (WTP) for diagnostic testing to find a genetic cause of DD from families of children with DD. A discrete choice experiment was used to obtain WTP values. When it was assumed that AGH resulted in twice as many diagnoses and a 1-week reduction in waiting time compared with conventional cytogenetic analysis, this study found that families were willing to pay up to CDN$1118 (95% confidence interval, $498-1788) for the expected benefit. These results support the conclusion that the introduction of AGH into the Canadian health care system may increase the perceived welfare of society, but future studies should examine the cost-benefit of AGH vs cytogenetic testing.

Real-world costing analysis for diffuse large B-cell lymphoma in British Columbia.

Introduction: Diffuse large B-cell lymphoma (dlbcl) accounts for 30%-40% of all non-Hodgkin lymphomas. Approximately 60% of patients are cured with standard treatment. Targeted treatments are being investigated and might improve disease outcomes; however, their effect on cancer drug budgets will be significant. For the present study, we conducted an analysis of real-world costs for dlbcl patients treated in British Columbia, useful for health care system planning. Methods: Patient records from a retrospective cohort of patients diagnosed with dlbcl in British Columbia during 2004-2013 were anonymously linked across multiple administrative data sources: systemic therapy, radiotherapy, hospitalizations, oncologist services, outpatient medications, and fee-for-service physician services. Using generalized linear modelling regression, time-dependent costs (in 2015 Canadian dollars) were estimated in 6-month intervals over a 5-year period. The inverse probability weighting method was applied to account for censored observations. Nonparametric bootstrapping was used to estimate standard errors for the mean cost at each time interval. Results: The cohort consisted of 678 patients (5-year overall survival: 67%). Mean age at diagnosis was 64 ± 14 years; median follow-up was 3.2 years. Mean total cost of care was highest in the first 6 months after diagnosis ($29,120; 95% confidence interval: $28,986 to $29,170) and after disease progression ($18,480; 95% confidence interval: $15,187 to $24,772). Systemic therapy and hospitalization costs were the largest cost drivers. At each time interval, costs were observed to be positively skewed. Conclusions: Our results depict real-world costs for the treatment of dlbcl patients with standard chop-r therapy. Cost-model parameters are also provided for economic modelling of dlbcl interventions.

Community diagnosis counts.

Because of such validity-research deficits and the ceiling on agreement between instruments imposed by less-than-perfect reliability characteristics of each instrument, it is not appropriate to assume that the semistructured clinician interview is more valid than the epidemiologic interview. The Baltimore ECA site is uniquely situated to address this issue by comparing the outcome of subjects identified with current depression in the 1982 clinical reappraisal interview with those identified by the DIS at the same time to see if the 13-year follow-up is similar to that found over 16 years by Murphy et al. Where do we go from here in improving our diagnostic criteria for DSM-V, constructing better diagnostic instruments, and conducting the next generation of epidemiologic studies? Certainly the categorical diagnostic criteria themselves, without a dimensional symptom level, are never used in clinical treatment trials. Hence the "clinical significance" criteria of significant distress or disability added to DSM-IV should be further refined, with the possible addition of "staging" of disorders. The objective would be to provide a better indication of treatment need and clinical prognosis as in current cancer diagnostic assessments. For epidemiologic studies, the addition of symptom scales and disability assessments to the traditional categorical diagnoses should be helpful in developing community measures of treatment need. Different methods of assessment may be useful for diagnoses in which an impaired perception of reality occurs, such as schizophrenia. With some of these adjustments, it should be feasible to "count" those with clinically significant diagnoses in the community, and thus improve the validity and clinical utility of our diagnoses for predicting clinical course and responsiveness to specific treatments.

The de facto US mental health services system: a public health perspective.

The President's Commission on Mental Health has highlighted a heretofore unmet need for the linkage of data on the prevalence of mental disorder with national data on the use of mental health services. This study analyzes available epidemiological data and recent mental health services research findings to estimate the percent of the population with a mental disorder and the proportion utilizing various types of specialty mental health and general medical treatment settings. Provisional estimates indicate that at least 15% of the US population is affected by mental disorders in one year. In 1975, only one fifth of these were served in the specialty mental health sector, with about three fifths identified in the general medical (primary care) sector.

Specialist/generalist division of responsibility for patients with mental disorders.

The division of responsibility between general medical staff and mental specialists for care of persons with medical record diagnoses of mental disorders is documented in four organized health care settings. Rates of mental disorders identified in all departments ranged from 35.6 to 122.8 per 1,000 population. Specialty mental health departments treated most severe psychotic and personality disorders, plus transient situational disturbances, whereas neurotic, childhood behavior, and psychophysiological disorders received as much or greater attention in general medical departments. Mental disorder diagnoses were associated with greater patient use of general medical departments. However, joint specialty mental health/general medical treatment of these patients was associated with lower general medical department visit rates in all settings. Such joint care was facilitated by the low average visit frequency use of mental health departments. (2.2 to 8.9 visits per patient per year).

Age at onset of selected mental disorders in five community populations.

Using data collected in the National Institute of Mental Health Epidemiologic Catchment Area Program, we examined the reported age at onset of selected mental disorders using life table survival methods. The examination of hazard rates suggests that adolescence and young adulthood are important periods for the development of unipolar major depression, bipolar illness, phobias, and drug and alcohol abuse/dependence. Although there are limitations in using cross-sectional data for this purpose, the findings suggest the need for more attention to the development of mental disorders in childhood and adolescence.

Comparing age at onset of major depression and other psychiatric disorders by birth cohorts in five US community populations.

Using data collected in the National Institute of Mental Health (Rockville, Md) Epidemiologic Catchment Area Program, we examined the proposed hypothesis that there has been a shift in major depression to younger ages at onset, or increased prevalence in younger age periods, for recent birth cohorts. Life-table survival methods were used to examine the hazard rates for major depression as well as for other specific mental disorders. The findings are consistent with a gradual shift to increased rates for major depression between the ages of 15 and 19 years for Epidemiologic Catchment Area respondents born more recently. The findings also suggest a similar shift for drug abuse/dependence; similar but less pronounced changes were found for alcohol abuse/dependence and obsessive-compulsive disorder. However, in this study, bipolar disorder, panic disorder, and phobias did not exhibit a consistent increase in onset at younger ages. Further research is required to determine if the shifts in major depression, drug abuse/dependence, and possibly alcohol abuse/dependence are linked. It is important to note that these shifts to adolescent onset are occurring when nearly half the 31 million Americans without health insurance are aged 24 years or younger.

Congruence of service utilization estimates from the Epidemiologic Catchment Area Project and other sources.

Service utilization estimates for inpatient and ambulatory mental health care from the Epidemiologic Catchment Area Project were compared with similar estimates from other sources, principally the Center for Mental Health Services National Reporting Program. Generally, results showed closer correspondence between estimates of the number of persons who used inpatient care than of similar estimates for ambulatory mental health care. Subtotal estimates for the specialty alcohol/other drug abuse/mental health and health care sectors were more similar than were estimates for individual settings. The specialty sector subtotals showed only a 7% difference in patient counts for inpatient care and 13% for ambulatory care, with an 11% difference in visits for the latter. Generally, a reasonable level of congruence was observed, given pronounced differences in methods, procedures, and instruments. Future directions may be able to close data gaps and improve the quality of the national mental health services database.

Use of services by persons with mental and addictive disorders. Findings from the National Institute of Mental Health Epidemiologic Catchment Area Program.

The use of ambulatory and inpatient mental health and addiction services in the United States was estimated by means of data from the National Institute of Mental Health Epidemiologic Catchment Area Program standardized to the 1980 US census for adults 18 years of age and older. In a 1-year period, 22.8 million people used ambulatory services for mental or addictive disorder treatment; 54% of them had a current Diagnostic Interview Schedule/DSM-III mental disorder and another 37.4% had a history of psychiatric disorder or significant psychiatric symptoms. A total of 325.9 million ambulatory visits were made, and the average number of visits per treated person per year was 14.3. There were 1.4 million persons admitted to at least one inpatient mental health or addiction setting during a 1-year period; 80% of them had a current DIS/DSM-III disorder, and the remainder had a history of psychiatric disorder or significant psychiatric symptoms. Results were determined for specific mental and substance use diagnoses and service settings. Among treated persons with any mental or addictive disorder, the majority of visits were to mental and addictive disorders specialty settings (40.5% of total visits) and to support networks composed of friends, relatives, and self-help groups (37.0% of total visits). Although a large number of persons with mental and substance use disorders were seen in the general medical sector for mental health or addiction problems, they were seen less frequently and therefore made fewer visits to this sector (10.9% of total visits).

The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures.

The Composite International Diagnostic Interview (CIDI), written at the request of the World Health Organization/US Alcohol, Drug Abuse, and Mental Health Administration Task Force on Psychiatric Assessment Instruments, combines questions from the Diagnostic Interview Schedule with questions designed to elicit Present State Examination items. It is fully structured to allow administration by lay interviewers and scoring of diagnoses by computer. A special Substance Abuse Module covers tobacco, alcohol, and other drug abuse in considerable detail, allowing the assessment of the quality and severity of dependence and its course. This article describes the design and development of the CIDI and the current field testing of a slightly reduced "core" version. The field test is being conducted in 19 centers around the world to assess the interviews' reliability and its acceptability to clinicians and the general populace in different cultures and to provide data on which to base revisions that may be found necessary. In addition, questions to assess International Classification of Diseases, ninth revision, and the revised DSM-III diagnoses are being written. If all goes well, the CIDI will allow investigators reliably to assess mental disorders according to the most widely accepted nomenclatures in many different populations and cultures.

Utilization of health and mental health services by Los Angeles Mexican Americans and non-Hispanic whites.

Utilization of general medical and mental health services by respondents in the Los Angeles Epidemiologic Catchment Area (ECA) site was compared with that in three ECA sites studied previously (New Haven, Conn, Baltimore, and St Louis). Within the Los Angeles sample, Mexican-American patterns of utilization were compared with those for non-Hispanic whites. Los Angeles respondents were less likely than those at other ECA sites to make ambulatory health care visits and to be hospitalized for physical or mental health reasons. Mexican Americans were less likely than non-Hispanic whites to report ambulatory health care but were as likely to have been hospitalized. Six percent of Los Angeles respondents reported a recent mental-health-care visit as compared with 6% to 7% of respondents at the other ECA sites. However, among respondents with Diagnostic Interview Schedule DSM-III disorders diagnosed within the six months prior to the interview, a lower proportion made a mental health visit in Los Angeles (14%) compared with the other sites (16% to 20%). Of those who made a mental-health-care visit, Los Angeles respondents with a recently diagnosed disorder were more likely than comparable respondents at the other ECA sites to visit a mental health specialist rather than a general medical care provider. Mexican Americans with a recently diagnosed mental disorder were only half as likely as non-Hispanic whites (11% vs 22%, respectively) to have made a mental health visit. However, when Mexican Americans with Diagnostic Interview Schedule/DSM-III did make a mental health visit, they were as likely as non-Hispanic whites to see a mental health specialist.

Use of general medical care services by persons with mental disorders.

Data are presented on the medical diagnoses and the type of general medical services used by persons with mental disorder diagnoses. This study is based on the 1975 experience of registrants in four medical programs contained in three organizational settings. The data on services were retrieved from each program's automated date system. The percent of patients seen in general medical departments receiving a mental disorder diagnosis ranged from 4.8% to 13.6% among the four programs. Patients with mental disorder diagnoses visit general medical departments from 11/2 to two times as frequently as patients without such diagnoses. Persons with a diagnosed mental disorder are likely to receive care for conditions in more International Classification of Diseases categories than other patients, and are more likely to receive a diagnosis for ill-defined conditions, signs, and symptoms.

Lifetime prevalence of specific psychiatric disorders in three sites.

Lifetime rates are presented for 15 DSM-III psychiatric diagnoses evaluated in three large household samples on the basis of lay interviewers' use of the Diagnostic Interview Schedule. The most common diagnoses were alcohol abuse and dependence, phobia, major depressive episode, and drug abuse and dependence. Disorders that most clearly predominated in men were antisocial personality and alcohol abuse and dependence. Disorders that most clearly predominated in women were depressive episodes and phobias. The age group with highest rates for most disorders was found to be young adults (aged 25 to 44 years). Correlates with race, education, and urbanization are presented.

The NIMH Epidemiologic Catchment Area program. Historical context, major objectives, and study population characteristics.

The National Institute of Mental Health multisite Epidemiologic Catchment Area (ECA) program is described in the context of four previous psychiatric epidemiologic surveys that included a combined total of 4,000 subjects from Stirling County, the Baltimore Morbidity Study, Midtown Manhattan, and the New Haven third-wave survey. The ECA program is distinguished by its sample size of at least 3,500 subjects per site (about 20,000 total); the focus on Diagnostic Interview Schedule--defined DSM-III mental disorders; the one-year reinterview-based longitudinal design to obtain incidence and service use data; the linkage of epidemiologic and health service use data; and the replication of design and method in multiple sites. Demographic characteristics of community and sample populations are provided for New Haven, Conn, Baltimore, and St Louis.

Progress toward achieving a common language in psychiatry. Results from the field trial of the clinical guidelines accompanying the WHO classification of mental and behavioral disorders in ICD-10.

In preparing for the 10th revision of the International Classification of Diseases (ICD-10), the Division of Mental Health of the World Health Organization organized an international field trial to help evaluate draft clinical descriptions and diagnostic guidelines that were produced to facilitate use of the chapter dealing with mental and behavioral disorders. These clinical guidelines were prepared in equivalent versions in most of the world's widely spoken languages. The field trial aimed to obtain data that would help in assessing whether the classification fits the diagnoses made in different countries, whether it is easy to use, and whether psychiatrists after a short period of familiarization with the classification can reach agreement about their diagnoses and classification. The field trial was carried out at 112 clinical centers in 39 countries by 711 clinicians who conducted 15,302 individual assessments. The trial included joint clinical assessments of patients and case history exercises. The results of the joint assessment part of the trial are reported here. Most clinicians reported that the draft document was easy to use and that the classification provided a good fit for the vast majority of the clinical conditions encountered. While interrater reliability was satisfactory for most categories, some (for example, those dealing with personality disorders) were somewhat difficult to use, and reliability of assignment for those was lower. The trial demonstrated that the ICD-10 chapter dealing with mental and behavioral disorders is on the whole suitable for general use. It provided valuable indications about changes needed for subsequent versions and demonstrated the feasibility of large-scale international research on classification and diagnosis in psychiatry.

The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services.

After initial interviews with 20,291 adults in the National Institute of Mental Health Epidemiologic Catchment Area Program, we estimated prospective 1-year prevalence and service use rates of mental and addictive disorders in the US population. An annual prevalence rate of 28.1% was found for these disorders, composed of a 1-month point prevalence of 15.7% (at wave 1) and a 1-year incidence of new or recurrent disorders identified in 12.3% of the population at wave 2. During the 1-year follow-up period, 6.6% of the total sample developed one or more new disorders after being assessed as having no previous lifetime diagnosis at wave 1. An additional 5.7% of the population, with a history of some previous disorder at wave 1, had an acute relapse or suffered from a new disorder in 1 year. Irrespective of diagnosis, 14.7% of the US population in 1 year reported use of services in one or more component sectors of the de facto US mental and addictive service system. With some overlap between sectors, specialists in mental and addictive disorders provided treatment to 5.9% of the US population, 6.4% sought such services from general medical physicians, 3.0% sought these services from other human service professionals, and 4.1% turned to the voluntary support sector for such care. Of those persons with any disorder, only 28.5% (8.0 per 100 population) sought mental health/addictive services. Persons with specific disorders varied in the proportion who used services, from a high of more than 60% for somatization, schizophrenia, and bipolar disorders to a low of less than 25% for addictive disorders and severe cognitive impairment. Applications of these descriptive data to US health care system reform options are considered in the context of other variables that will determine national health policy.

Limitations of diagnostic criteria and assessment instruments for mental disorders. Implications for research and policy.

During the past 2 decades, psychiatric epidemiological studies have contributed a rapidly growing body of scientific knowledge on the scope and risk factors associated with mental disorders in communities. Technological advances in diagnostic criteria specificity and community case-identification interview methods, which made such progress feasible, now face new challenges. Standardized methods are needed to reduce apparent discrepancies in prevalence rates between similar population surveys and to differentiate clinically important disorders in need of treatment from less severe syndromes. Reports of some significant differences in mental disorder rates from 2 large community surveys conducted in the United States--the Epidemiologic Catchment Area study and the National Comorbidity Survey--provide the basis for examining the stability of methods in this field. We discuss the health policy implications of discrepant and/or high prevalence rates for determining treatment need in the context of managed care definitions of "medical necessity."