Olmstead's implementation: Differences in enforcement approaches.

Olmstead v. L.C. ex rel Zimring (1999) was a landmark U.S. Supreme Court decision holding that unjustified segregation of people with disabilities is impermissible discrimination; specifically, if the clinician and client believe community integration to be appropriate, the state must have reasonable accommodations in place for the client to be in the community. Enforcement of the Olmstead decision for people with serious mental illness (SMI) has taken many shapes, from the U.S. Department of Justice's (DOJ) settlement agreements requiring substantive development of community mental health services and aggressive community integration protocols, to the Third Circuit approach which requires only lower census numbers in the state psychiatric hospital (SPH). The question of whether Olmstead is being differentially enforced is addressed in an empirical, qualitative analysis of legal documents, including court opinions and settlement agreements. Through legal research spanning all U.S. jurisdictions, five distinct Olmstead enforcement approaches in ten different states were identified. The enforcement approaches are described, and limitations and future directions are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Ideal and real treatment planning processes for people with serious mental illness in public mental health care.

Treatment planning processes are a fundamental component of evidence-based practice in mental health for people with serious mental illness (SMI), who often present with complex concerns and require an interdisciplinary treatment team. It is unclear how well treatment planning practices in usual care settings for SMI adhere to best practices guidelines. In this study, we used qualitative methods to increase understanding of typical treatment planning practices. Twelve mental health providers completed a participatory dialogue focused on discussing perceptions of ideal and real treatment planning processes. Content analysis of the transcription from the dialogue was used to identify major themes and subthemes. Analysis revealed 6 primary themes with 23 subthemes. Providers described the ideal treatment planning process as dynamic and collaborative, including thorough assessment and inclusion of all stakeholders including the consumer, providers, and family members. Real treatment planning was described as directed by institutional and regulatory needs, resulting in treatment plans that were not personalized and not communicated to frontline staff or the consumer. These results indicate that providers have a strong understanding of evidence-based principles of treatment decision-making. However, actual treatment planning processes rarely live up to those principles. Providers identified several obstacles to enacting best practices. Although many obstacles were system-level, providers themselves also contributed to the gap between ideal and real treatment planning. Additional training and education may help to close this gap. Consumer self-advocacy is also important, given that providers often see themselves as lacking agency to make changes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Collaborative decision skills training: Feasibility and preliminary outcomes of a novel intervention.

Increasing consumer empowerment and agency in treatment decision-making is a priority for improving recovery among people with serious mental illness (SMI), as it is associated with a number of positive outcomes, including improved treatment engagement and satisfaction. Although there are many tools to promote initiation of shared decision-making by providers, there are few tools empowering consumers to independently initiate collaborative decision-making (CDM). Therefore, this study tests the feasibility of a novel skills training intervention for outpatients with SMI, collaborative decision skills training (CDST). Twenty-one consumers with SMI currently receiving community-based day services participated in CDST. Four areas of feasibility were assessed-acceptability, demand, practicality, and preliminary evidence of efficacy. Feasibility results were favorable, including high acceptability and practicality. Demand results were mixed: rates of attendance were high and attrition was low, but participants did not complete homework as often as expected. Finally, there was evidence CDST has a positive impact on targeted outcomes; participants reported an increased sense of personal recovery, and displayed improvements in both knowledge and skills targeted by CDST. CDST is feasible to implement with fidelity and is received well by participants. Next steps include larger controlled trials of CDST, which will better inform efficacy and implementation related questions. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Feasibility test of autotrophic denitrification of industrial wastewater in sequencing batch and static granular bed reactors.

In order to evaluate the efficacy of using reduced sulfur species in lieu of conventional substrates, a sequencing batch reactor (SBR) was used to develop an autotrophic denitrifying culture which in turn was used to seed a static granular bed reactor (SGBR) for continuous flow treatment. Both bioreactors were able to quickly acclimate to the anoxic environment and achieve stable autotrophic denitrification within several weeks of being placed in operation. The seed for the SBR was obtained from operating basins at the Cedar Rapids plant. MiSeq analysis showed the presence of the autotrophic denitrifier Thiobacillus in the seed from the sulfur oxidation basin; however, Shinella and Sulfurovum became the dominant autotrophic denitrifiers in the SBR. Both the SBR and SGBR achieved excellent nitrate removal (i.e., >95%) with stoichiometric amounts of thiosulfate added to the synthetic influent. The results of this feasibility study suggest that anaerobic granules from the UASB at the plant serve as good seed biomass for autotrophic denitrification when augmented by sulfur oxidation basin and sulfide scrubber biomass, and that reduced sulfur species at the plant (or augmented with an external sulfur source) can serve as electron donors for nearly complete denitrification. PRACTITIONER POINTS: Autotrophic denitrification of industrial wastewater was investigated to evaluate reduced sulfur species as electron donor for nitrogen removal. An autotrophic denitrifying culture was cultivated in an SBR, and continuous autotrophic denitrification was accomplished in an SGBR. No increase in head loss was observed in the SGBR, and it was able to operate without the need for backwashing in more than 200 days of operation. Reduced sulfur was demonstrated to be a sufficient electron donor for nearly complete denitrification. MiSeq analysis resolved primary species responsible for autotrophic denitrification in this study.

Psychosocial and functional contributors to personal recovery in serious mental illness.

Background: Although recovery-oriented services have been conceptualized to improve personal recovery, related research often focuses on measures of clinical recovery. Identifying the relationships between personal recovery, clinical recovery, and psychosocial variables will inform service components and outcome measurement in recovery-oriented services. Aims: This study sought to determine the connection between personal recovery and two sets of potential contributors: psychosocial variables (i.e., empowerment, resilience, and consumer involvement) and functional indicators of clinical recovery. Method: These relationships were examined by analyzing survey data collected from 266 consumers who are receiving public mental health services in the United States. Results: Empowerment, resilience and psychological involvement were associated with personal recovery. Clinical recovery did not uniquely contribute to personal recovery once psychosocial factors were accounted for. Interactions revealed that the relationship between psychological involvement and personal recovery was stronger for those who had been recently hospitalized, and for those with relatively greater resilience. Conclusions: Results indicate that personal recovery is an essential outcome measure for recovery-oriented services that cannot be replaced by clinical recovery outcome measurement. Additionally, empowerment, resilience, and consumer involvement are key components of recovery, which suggests that services and outcome measures should prioritize incorporation of these constructs.

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification.

BACKGROUND: By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. METHODS: We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing-based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single-nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation. RESULTS: Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity. CONCLUSIONS: Validated high-fidelity identification of different variant types-especially for diseases with complicated molecular genetics-maximizes at-risk couple detection.

Systematic design and comparison of expanded carrier screening panels.

PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.

Development and validation of a 36-gene sequencing assay for hereditary cancer risk assessment.

The past two decades have brought many important advances in our understanding of the hereditary susceptibility to cancer. Numerous studies have provided convincing evidence that identification of germline mutations associated with hereditary cancer syndromes can lead to reductions in morbidity and mortality through targeted risk management options. Additionally, advances in gene sequencing technology now permit the development of multigene hereditary cancer testing panels. Here, we describe the 2016 revision of the Counsyl Inherited Cancer Screen for detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy number variants (CNVs) in 36 genes associated with an elevated risk for breast, ovarian, colorectal, gastric, endometrial, pancreatic, thyroid, prostate, melanoma, and neuroendocrine cancers. To determine test accuracy and reproducibility, we performed a rigorous analytical validation across 341 samples, including 118 cell lines and 223 patient samples. The screen achieved 100% test sensitivity across different mutation types, with high specificity and 100% concordance with conventional Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). We also demonstrated the screen's high intra-run and inter-run reproducibility and robust performance on blood and saliva specimens. Furthermore, we showed that pathogenic Alu element insertions can be accurately detected by our test. Overall, the validation in our clinical laboratory demonstrated the analytical performance required for collecting and reporting genetic information related to risk of developing hereditary cancers.

Noninvasive prenatal screening at low fetal fraction: comparing whole-genome sequencing and single-nucleotide polymorphism methods.

OBJECTIVE: Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies. METHODS: Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations. RESULTS: The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples. CONCLUSION: The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. © 2017 Counsyl Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates.

OBJECTIVE: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences. METHODS: A total of 262 399 individuals with no known indication or increased probability of SLOS carrier status, primarily US based, were screened for SLOS mutations as part of an expanded carrier screening panel. Results were retrospectively analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature were then compared with these data to estimate the effect of SLOS on fetal survival. RESULTS: Smith-Lemli-Opitz syndrome carrier frequency is highest in Ashkenazi Jews (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence with that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience prenatal demise. CONCLUSION: Smith-Lemli-Opitz syndrome is relatively frequent in certain populations and, because of its impact on prenatal and postnatal morbidity and mortality, merits consideration for routine screening. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Group Testing Approach for Trinucleotide Repeat Expansion Disorder Screening.

BACKGROUND: Fragile X syndrome (FXS, OMIM #300624) is an X-linked condition caused by trinucleotide repeat expansions in the 5' UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. FXS testing is commonly performed in expanded carrier screening and has been proposed for inclusion in newborn screening. However, because pathogenic alleles are long and have low complexity (>200 CGG repeats), FXS is currently tested by a single-plex electrophoresis-resolved PCR assay rather than multiplexed approaches like next-generation sequencing or mass spectrometry. In this work, we sought an experimental design based on nonadaptive group testing that could accurately and reliably identify the size of abnormally expanded FMR1 alleles of males and females. METHODS: We developed a new group testing scheme named StairCase (SC) that was designed to the constraints of the FXS testing problem, and compared its performance to existing group testing schemes by simulation. We experimentally evaluated SC's performance on 210 samples from the Coriell Institute biorepositories using pooled PCR followed by capillary electrophoresis on 3 replicates of each of 3 pooling layouts differing by the mapping of samples to pools. RESULTS: The SC pooled PCR approach demonstrated perfect classification of samples by clinical category (normal, intermediate, premutation, or full mutation) for 90 positives and 1800 negatives, with a batch of 210 samples requiring only 21 assays. CONCLUSIONS: Group testing based on SC is an implementable approach to trinucleotide repeat expansion disorder testing that offers ≥10-fold reduction in assay costs over current single-plex methods.

Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening.

IMPORTANCE: Screening for carrier status of a limited number of single-gene conditions is the current standard of prenatal care. Methods have become available allowing rapid expanded carrier screening for a substantial number of conditions. OBJECTIVES: To quantify the modeled risk of recessive conditions identifiable by an expanded carrier screening panel in individuals of diverse racial and ethnic backgrounds and to compare the results with those from current screening recommendations. DESIGN, SETTING, AND PARTICIPANTS: Retrospective modeling analysis of results between January 1, 2012, and July 15, 2015, from expanded carrier screening in reproductive-aged individuals without known indication for specific genetic testing, primarily from the United States. Tests were offered by clinicians providing reproductive care. EXPOSURES: Individuals were tested for carrier status for up to 94 severe or profound conditions. MAIN OUTCOMES AND MEASURES: Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories; there were 11 categories with >5000 samples) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease. Severe conditions were defined as those that if left untreated cause intellectual disability or a substantially shortened lifespan; profound conditions were those causing both. RESULTS: The study included 346,790 individuals. Among major US racial/ethnic categories, the calculated frequency of fetuses potentially affected by a profound or severe condition ranged from 94.5 per 100,000 (95% CI, 82.4-108.3 per 100,000) for Hispanic couples to 392.2 per 100,000 (95% CI, 366.3-420.2 per 100,000) for Ashkenazi Jewish couples. In most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines (Mann-Whitney P < .001). For Northern European couples, the 2 professional guidelines-based screening panels modeled 55.2 hypothetical fetuses affected per 100,000 (95% CI, 51.3-59.3 per 100,000) and the expanded carrier screening modeled 159.2 fetuses per 100,000 (95% CI, 150.4-168.6 per 100,000). Overall, relative to expanded carrier screening, guideline-based screening ranged from identification of 6% (95% CI, 4%-8%) of hypothetical fetuses affected for East Asian couples to 87% (95% CI, 84%-90%) for African or African American couples. CONCLUSIONS AND RELEVANCE: In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies. Prospective studies comparing current standard-of-care carrier screening with expanded carrier screening in at-risk populations are warranted before expanded screening is adopted.

Design and validation of a next generation sequencing assay for hereditary BRCA1 and BRCA2 mutation testing.

Hereditary breast and ovarian cancer syndrome, caused by a germline pathogenic variant in the BRCA1 or BRCA2 (BRCA1/2) genes, is characterized by an increased risk for breast, ovarian, pancreatic and other cancers. Identification of those who have a BRCA1/2 mutation is important so that they can take advantage of genetic counseling, screening, and potentially life-saving prevention strategies. We describe the design and analytic validation of the Counsyl Inherited Cancer Screen, a next-generation-sequencing-based test to detect pathogenic variation in the BRCA1 and BRCA2 genes. We demonstrate that the test is capable of detecting single-nucleotide variants (SNVs), short insertions and deletions (indels), and copy-number variants (CNVs, also known as large rearrangements) with zero errors over a 114-sample validation set consisting of samples from cell lines and deidentified patient samples, including 36 samples with BRCA1/2pathogenic germline mutations.

Understanding the Basics of NGS: From Mechanism to Variant Calling.

Identifying disease-causing mutations in DNA has long been the goal of genetic medicine. In the last decade, the toolkit for discovering DNA variants has undergone rapid evolution: mutations that were historically discovered by analog approaches like Sanger sequencing and multiplex ligation-dependent probe amplification ("MLPA") can now be decoded from a digital signal with next-generation sequencing ("NGS"). Given the explosive growth of NGS-based tests in the clinic, it is of the utmost importance that medical practitioners have a fundamental understanding of the newest NGS methodologies. To that end, here we provide a very basic overview of how NGS works, with particular emphasis on the close resemblance between the underlying chemistry of Sanger sequencing and NGS. Using a pair of simple analogies, we develop an intuitive framework for understanding how high-confidence detection of single-nucleotide polymorphisms, indels, and large deletions/duplications is possible with NGS alone.

The relevance and implications of organizational involvement for serious mental illness populations.

Consumer involvement has gained greater prominence in serious mental illness (SMI) because of the harmonious forces of new research findings, psychiatric rehabilitation, and the recovery movement. Previously conceived subdomains of consumer involvement include physical involvement, social involvement, and psychological involvement. We posit a fourth subdomain, organizational involvement. We have operationally defined organizational involvement as the involvement of mental health consumers in activities and organizations that are relevant to the mental health aspect of their identities from an individual to a systemic level across arenas relevant to mental health. This study surveyed adults with SMI regarding their current level of organizational involvement along with their preferences and beliefs about organizational involvement. Additionally, a path model was conducted to understand the relationships between domains of consumer involvement. Although participants reported wanting to be involved in identified organizational involvement activities and believing it was important to be involved in these kinds of activities, organizational involvement was low overall. The path model indicated that psychological involvement among other factors influence organizational involvement, which informed our suggestions to improve organizational involvement among people with SMI. Successful implementation must be a thoroughly consumer-centered approach creating meaningful and accessible involvement opportunities. Our study and prior studies indicate that organizational involvement and other subdomains of consumer involvement are key to the health and wellbeing of consumers, and therefore greater priority should be given to interventions aimed at increasing these essential domains.

Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels.

Professional guidelines dictate that disease severity is a key criterion for carrier screening. Expanded carrier screening, which tests for hundreds to thousands of mutations simultaneously, requires an objective, systematic means of describing a given disease's severity to build screening panels. We hypothesized that diseases with characteristics deemed to be of highest impact would likewise be rated as most severe, and diseases with characteristics of lower impact would be rated as less severe. We describe a pilot test of this hypothesis in which we surveyed 192 health care professionals to determine the impact of specific disease phenotypic characteristics on perceived severity, and asked the same group to rate the severity of selected inherited diseases. The results support the hypothesis: we identified four "Tiers" of disease characteristics (1-4). Based on these responses, we developed an algorithm that, based on the combination of characteristics normally seen in an affected individual, classifies the disease as Profound, Severe, Moderate, or Mild. This algorithm allows simple classification of disease severity that is replicable and not labor intensive.

Characterization of recycled rubber media for hydrogen sulphide (H2S) control.

Hydrogen sulphide (H2S) adsorption capacities on recycled rubber media, tyre-derived rubber particle (TDRP), and other rubber material (ORM) have been evaluated. As part of the research, densities, moisture contents, and surface properties of TDRP and ORM have been determined. The research team findings show that TDRP and ORM are more particulate in nature and not highly porous-like activated carbon. The characteristics of surface area, pore size, and moisture content support chemisorption on the macrosurface rather than physical adsorption in micropores. For example, moisture content is essential for H2S adsorption on ORM, and an increase in moisture content results in an increase in adsorption capacity.

Detection of carriers in the Ashkenazi Jewish population: an objective comparison of high-throughput genotyping versus gene-by-gene testing.

BACKGROUND: High-throughput genotyping allows rapid identification of targeted mutations at a fraction of the cost of current gene-by-gene testing methodologies. An objective comparison of the two methodologies allows providers to assess the clinical validity/utility of high-throughput carrier screening and establish a comfort level with new genomic technologies. AIM: To verify that high-throughput genotyping accurately determines patient carrier status, DNA samples from previously identified carriers (n=31) of Ashkenazi Jewish genetic diseases were anonymized and submitted for retesting by high-throughput genotyping. RESULTS: The results were 100% concordant (95% CI: 0.998-1), demonstrating that high-throughput genotyping assays accurately identify carriers of targeted mutations in the Ashkenazi Jewish population. In addition, carrier status for diseases and mutations not previously tested was uncovered using the high-throughput assay. CONCLUSIONS: High-throughput genotyping is a cost-effective and clinically valid approach to carrier screening. The use of a broader screen for Ashkenazi Jewish individuals increases the detection of carriers in this population.