Adapting a group-based, multimodal aphasia treatment for telehealth - co-design of M-MAT Tele.

Multi-Modality Aphasia Treatment (M-MAT) is an effective group intervention for post-stroke aphasia. M-MAT employs interactive card games and the modalities of gesture, drawing, reading, and writing to improve spoken language. However, there are challenges to implementation of group interventions such as M-MAT, particularly for those who cannot travel or live in rural areas. To maximise access to this effective treatment, we aimed to adapt M-MAT to telehealth format (M-MAT Tele). The Human-Centred Design Framework was utilized to guide the adaptation approach. We identified the intended context of use (outpatient/community rehabilitation) and the stakeholders (clinicians, people with aphasia, health service funders). People with aphasia and practising speech pathologists were invited to co-design M-MAT Tele in a series of iterative workshops, to ensure the end product was user-friendly and clinically feasible. The use of co-design allowed us to understand the hardware, software and other constraints and preferences of end users. In particular, clinicians (n = 3) required software compatible with a range of telehealth platforms and people with aphasia (n = 3) valued solutions with minimal technical demands and costs for participants. Co-design within the Human-Centred Design Framework led to a telehealth solution compatible with all major telehealth platforms, with minimal hardware or software requirements. Pilot testing is underway to confirm acceptability of M-MAT Tele to clinicians and people with aphasia, aiming to provide an effective, accessible tool for aphasia therapy in telehealth settings.

Comprehensive quality assessment for aphasia rehabilitation after stroke: protocol for a multicentre, mixed-methods study.

INTRODUCTION: People with aphasia following stroke experience disproportionally poor outcomes, yet there is no comprehensive approach to measuring the quality of aphasia services. The Meaningful Evaluation of Aphasia SeRvicES (MEASuRES) minimum dataset was developed in partnership with people with lived experience of aphasia, clinicians and researchers to address this gap. It comprises sociodemographic characteristics, quality indicators, treatment descriptors and outcome measurement instruments. We present a protocol to pilot the MEASuRES minimum dataset in clinical practice, describe the factors that hinder or support implementation and determine meaningful thresholds of clinical change for core outcome measurement instruments. METHODS AND ANALYSIS: This research aims to deliver a comprehensive quality assessment toolkit for poststroke aphasia services in four studies. A multicentre pilot study (study 1) will test the administration of the MEASuRES minimum dataset within five Australian health services. An embedded mixed-methods process evaluation (study 2) will evaluate the performance of the minimum dataset and explore its clinical applicability. A consensus study (study 3) will establish consumer-informed thresholds of meaningful change on core aphasia outcome constructs, which will then be used to establish minimal important change values for corresponding core outcome measurement instruments (study 4). ETHICS AND DISSEMINATION: Studies 1 and 2 have been registered with the Australian and New Zealand Clinical Trial Registry (ACTRN12623001313628). Ethics approval has been obtained from the Royal Brisbane and Women's Hospital (HREC/2023/MNHB/95293) and The University of Queensland (2022/HE001946 and 2023/HE001175). Study findings will be disseminated through peer-reviewed publications, conference presentations and engagement with relevant stakeholders including healthcare providers, policy-makers, stroke and rehabilitation audit and clinical quality registry custodians, consumer support organisations, and individuals with aphasia and their families.

Allied Health Clinicians' Uptake of Evidence in Stroke Rehabilitation: A Systematic Review of Determinants Targeted in Implementation Studies.

OBJECTIVE: This study aimed to determine whether targeting specific implementation determinants is associated with allied health clinicians' uptake of evidence when implemented within stroke rehabilitation settings. DATA SOURCES: 7 key databases were searched to identify articles published between 1990 and 2022 for inclusion. Reference lists of relevant articles were hand searched. STUDY SELECTION: Studies were independently screened by 2 authors and included if the implementation intervention targeted allied health clinical practice in any stroke rehabilitation context and reported at least 1 quantitative measure of evidence uptake. Thirty studies met inclusion criteria. DATA EXTRACTION: Data were independently extracted by the first and second author. Implementation outcomes for each study were categorized as either mostly successful, partially successful, or not successful based on the degree of evidence uptake achieved. Determinants targeted were categorized using the Consolidated Framework for Implementation Research (CFIR). DATA SYNTHESIS: Patterns between the degree of evidence uptake and determinants targeted across studies were analyzed by the first and second authors in 1 of 3 groups: A (pre-post statistical analysis), B (pre-post descriptive analysis), or C (post-only descriptive analysis). Patterns between evidence uptake and determinants targeted were first identified within groups A and B, with group C consulted to support findings. All studies categorized as "mostly successful" targeted facilitation in combination with establishing face-to-face networks and communication strategies. Conversely, no studies rated "not successful" targeted either of these determinants. Studies rated "partially successful" targeted either 1, but seldom both, of these determinants. CONCLUSIONS: This review has provided descriptive evidence of determinants which may be important to target for allied health clinicians' uptake of evidence within stroke rehabilitation settings.

Profiling potential brewing yeast from forest and vineyard ecosystems.

The brewing ability of wild yeast strains obtained from forest and vineyards ecosystems was analysed and compared with commercial yeast strains. The selection of new yeast strains as a way to create new beer aromas and flavours and to use local strains to promote the proximity ingredients in brewing is a topic of interest in the craft beer sector. Seventy-six wild Saccharomyces and non-Saccharomyces isolates and eighteen control strains were evaluated for their enzymatic activity and brewing capacity. The early screening system was set up to profile their enzymatic activity, utilisation of wort sugars and the effect of hop acids and ethanol on yeast growth. The microvolume screening method allows a large number of samples to be studied at the same time, permitting an affordable and rapid characterization in a relatively short period of time. Twenty-eight strains were selected using this method and tested in small-scale fermentations. Finally, three of these strains, all belonging to the species Lachancea thermotolerans, showed great potential and adaptability to ferment different wort styles, although further studies will be necessary to test their possibilities as beer starters. Understanding yeast enzymatic profiles and the influence of beer ingredients on their fermentation activity provides a platform to select strains for further consideration in brewing research.

"It could bring down Greek life as a whole": Greek life members' perspectives on party culture, safety, responsibilities and consequences.

OBJECTIVE: Describe Greek life students' perspectives of party culture, safety, and College Sexual Violence (CSV) prevention. PARTICIPANTS: 27 US undergraduates: 5 fraternity underclassmen, 6 fraternity upperclassmen, 10 sorority underclassmen, 6 sorority upperclassmen. METHODS: Students participated in one of four focus groups, separately by gender and academic year. Facilitation guide addressed partying, sexual violence, and safety. RESULTS: Greek life members described partying preferences, perceived safety threats, and actions they took to party safely. University efforts to support safe partying were not universally viewed as helpful. CONCLUSIONS: Although Greek life students strive to create safe partying environments, there remain missed opportunities to mitigate risks related to CSV. The responsibility to ensure safe partying falls too heavily on students, resulting in universities missing opportunities to provide measures that promote safety while mitigating risks and potentially serious harms.

"Self-management has to be the way of the future": Exploring the perspectives of speech-language pathologists who work with people with aphasia.

PURPOSE: Healthcare models have incorporated self-management approaches to facilitate increased patient responsibility for chronic condition management. As aphasia is a chronic condition, self-management may be beneficial for people with aphasia; however, the possible impacts of the language disorder on self-management must be acknowledged and addressed. Speech-language pathologists would likely be principal providers of self-management support; therefore, their perspectives should be sought when considering development of aphasia self-management approaches. This study aims to explore speech-language pathologist perspectives of aphasia self-management. METHOD: In-depth, semi-structured interviews conducted with 15 speech-language pathologists in Australia. Interview data analysed using qualitative content analysis. RESULT: Aphasia self-management was viewed as a person- and family-centred approach enabling comprehensive long-term care for people with aphasia and promoting control, responsibility, and independence. Speech-language pathologists were seen to have a substantial role providing self-management support and consultation, and training was required to expand this role. Communication partners and peer support were highly valued. Personal and environmental factors may influence successful aphasia self-management. Differences between aphasia self-management and chronic condition self-management were considered. CONCLUSION: Self-management could facilitate long-term sustainable aphasia management. Aphasia self-management approaches should factor in how to maximise communication partner and peer support. Aphasia-friendly self-management resources are necessary.

"There are endless areas that they can use it for": speech-language pathologist perspectives of technology support for aphasia self-management.

BACKGROUND: Aphasia is a debilitating acquired language disorder that often persists as a chronic condition. However, long-term support options are scarce, necessitating the consideration of alternative approaches. Chronic condition self-management approaches, which aim to build self-efficacy and empower people to take responsibility for the day-to-day management of their health condition, may benefit people with aphasia (PwA). Technology is widely used in chronic condition self-management and investigation is required to determine whether it could play a role in aphasia self-management. OBJECTIVE: This study aimed to explore speech-language pathologist (SLP) perspectives on the potential use of technology to support aphasia self-management. METHODS: A qualitative study was conducted with 15 SLPs using semi-structured interviews. Qualitative content analysis was applied to verbatim transcripts to identify codes, categories, and sub-themes which were developed into themes. RESULTS: Three themes were identified: (1) technology supports holistic aphasia self-management by providing additional avenues for service delivery, overall communication, and learning opportunities thus enhancing independence and life participation; (2) SLP and communication partner (CP) assistance can support PwA to use technology for aphasia self-management; (3) considerations and potential barriers to PwA use of technology for aphasia self-management. CONCLUSIONS: Technology can support aphasia self-management by expanding service delivery options, allowing for increased frequency and intensity of therapy practise, and facilitating communication and participation. Personal, professional, and organizational barriers should be addressed in the development of technology-enabled aphasia self-management approaches. SLPs and CPs can offer PwA assistance with technology but may themselves need additional support. Solutions for identified barriers should be considered, such as providing training in the use of technology and implementing aphasia-friendly modifications.IMPLICATIONS FOR REHABILITATIONSelf-management approaches are being explored in the area of aphasia management as a means of offering a holistic, sustainable intervention option that meets the long-term needs of people with aphasia.A range of technology-based resources are currently used in chronic condition self-management and in aphasia therapy, and there are many possibilities for the use of technology in aphasia self-management approaches.Speech-language pathologists identified that technology could facilitate aphasia self-management by expanding service delivery options (e.g., real-time and asynchronous telepractice), enabling increased frequency and intensity of therapy through providing a means of independent practise, offering options for augmentative alternative communication, and enhancing life participation by supporting social communication and daily tasks.,Speech-language pathologists are interested in using technology for aphasia self-management; however, barriers related to organizational policies, individual experience and confidence using technology, and technology itself must be addressed.

People with aphasia share their views on self-management and the role of technology to support self-management of aphasia.

PURPOSE: Self-management can lead to increased self-efficacy and improved quality of life for individuals with chronic conditions; however, there is little research exploring how self-management approaches can be used for chronic communication disorders, such as aphasia. Modifications to self-management approaches would be required to accommodate for aphasia; therefore, the input of people with aphasia (PwA) should be sought. The aims of the present study were: (1) To investigate and document the experiences and perspectives of PwA regarding self-management; (2) To explore how technology can be used to support aphasia self-management. MATERIALS AND METHODS: In-depth, semi-structured interviews were conducted with 26 PwA living in Australia. Qualitative content analysis was used to analyse interview data. RESULTS: Analysis resulted in six themes: (1) In self-management, PwA take control of life with aphasia and assume responsibility for engaging in opportunities to improve overall communication; (2) Community aphasia groups are important enablers of self-management because they facilitate peer support; (3) Communication partners (CPs) provide multifaceted support in aphasia self-management; (4) SLPs provide integrated support and coordination in aphasia self-management; (5) Technology supports PwA to self-manage speech therapy and communication in daily life; (6) Psychological and physical health issues and societal factors may impact aphasia self-management abilities. CONCLUSION: From the perspective of PwA, aphasia self-management involves enhancing skills enabling communication and life participation. PwA are central to aphasia self-management, with support provided by CPs, peers, and SLPs. Technology has a range of applications in aphasia self-management. PwA identified potential personal and contextual barriers that may impact self-management.IMPLICATIONS FOR REHABILITATIONFor people with aphasia, engaging in conversation and social interaction are primary means of managing/improving communicative life participation; therefore, this should be a key focus of aphasia self-management programs.Aphasia self-management approaches should maximise the use of available support and provide tailored information, education, and training in the area of self-management to key stakeholders (people with aphasia, communication partners, and speech-language pathologists).People with aphasia should be supported to use technology for aphasia self-management, encompassing communication specific and daily life use.People with aphasia should be heavily involved in the development of structured aphasia self-management approaches.

Communication partner perspectives of aphasia self-management and the role of technology: an in-depth qualitative exploration.

PURPOSE: "Self-management" empowers individuals to take responsibility for their healthcare through skill-building, personal growth, and self-efficacy related to chronic health condition management. Self-management approaches may benefit people with aphasia (PwA); however, PwA are often excluded from stroke self-management research and there is no published research reporting on aphasia-specific self-management programs. Communication partners (CPs) are involved in the rehabilitation and day-to-day lives of PwA, thus giving them unique insights and knowledge of PwA needs. The present study aimed to investigate CP experiences and perspectives regarding aphasia self-management and to explore CP perceptions of the use of technology in aphasia self-management. METHODS: In-depth, semi-structured interviews with 14 CPs living in Australia. Interview data was analysed using qualitative content analysis. RESULTS: Analysis revealed six core themes: (1) aphasia self-management is embedded into everyday life, (2) CPs provide comprehensive self-management support, (3) speech-language pathologists (SLPs) provide tools and support to enable PwA to self-manage, (4) aphasia self-management can be enhanced by technological supports, (5) potential positive outcomes of aphasia self-management, and (6) factors influencing successful aphasia self-management. CONCLUSIONS: Aphasia self-management programs should focus on individual needs, functional communication in daily life, and social interaction. PwA and CPs are central to these programs, assisted by SLPs. Technology should be explored to augment aphasia self-management.Implications for RehabilitationCommunication partners suggest that people with aphasia are already engaging in aspects of self-management and that more formal aphasia-specific self-management approaches may be beneficial.Dedicated aphasia self-management programs should be situated in daily life with a focus on functional communication, life participation, confidence, and independence.Communication partners, speech-language pathologists, and technology are key support sources for aphasia self-management.Further input should be sought from communication partners in the development of aphasia self-management programs.

Setting a prioritized agenda to drive speech-language therapy research in health.

BACKGROUND: Prioritized research agendas are viewed internationally as an important method for ensuring that health research meets actual areas of clinical need. There is growing evidence for speech-language therapy-prioritized research agendas, particularly in disorder-specific areas. However, there are few general research priority agendas to guide speech-language therapy research. AIMS: To collaboratively develop a prioritized research agenda for an Australian public health context with clinical speech-language therapists (SLTs), academic SLTs and consumers of speech-language therapy services. METHODS & PROCEDURES: An initial stimulus list of potential research areas for prioritization was collected from SLTs via an online survey. Two categories (service delivery and expanded scope of practice) were selected from this list for prioritization due to their relevance across multiple health services. The Nominal Group Technique (NGT) was used to develop a prioritized research agenda for each of the two categories. One NGT session was conducted with each of the three participant groups (clinical SLTs, academic SLTs, consumers) for each category (total NGT sessions = six). The prioritization data for each group within each category were summed to give a single, ranked prioritized research agenda for each category. OUTCOMES & RESULTS: Two prioritized research agendas were developed. Within each agenda, SLTs and consumers prioritized a need for more research in areas related to specific practice areas (e.g., Alternative and Augmentative Communication, Communication Partner Training), as well as broader professional issues (e.g., telehealth, working with culturally and linguistically diverse families). CONCLUSIONS & IMPLICATIONS: The current findings support the need for funding proposals and targeted projects that address these identified areas of need. WHAT THIS PAPER ADDS: What is already known on this subject Evidence-based practice is a critical component of SLT practice. There is often a disconnect between the research evidence generated and areas of clinical need, and in some areas a lack of evidence. Prioritized research agendas can help drive research in areas of clinical need. What this paper adds to existing knowledge A collaborative, prioritized SLT research agenda was developed using the NGT according to the views of clinical SLTs, academic SLTs and consumers of speech-language therapy services in a conglomerate of public health services. SLTs and consumers identified a need for further research in specific areas of SLT practice as well as broader emerging professional issues What are the potential or actual clinical implications of this work? Targeted research projects funded on a large scale are required to address these identified areas of need. Other health services around the world could replicate this prioritization process to drive research in areas of clinical need.

Hear-Communicate-Remember: Feasibility of delivering an integrated intervention for family caregivers of people with dementia and hearing impairment via telehealth.

PURPOSE: To evaluate the feasibility of Hear-Communicate-Remember, a training programme developed for family caregivers of people with dementia and hearing impairment that integrated hearing, communication and memory strategies, which was intended to be delivered via telehealth. MATERIALS AND METHODS: Participants included six dyads consisting of adults with dementia and hearing impairment and their family caregivers. Data collection involved a combination of semi-structured interviews, self-report questionnaires and field notes. RESULTS: Analysis of the qualitative interviews revealed four themes: appropriateness of intervention resources, considerations for the delivery of intervention via telehealth, knowledge and application of intervention strategies, and impact of the intervention on day-to-day life. Results from the satisfaction survey indicated that caregiver participants were mostly satisfied with all aspects of the intervention except the use of some technological components. The field notes described challenges with implementation via telehealth. CONCLUSIONS: Future research involving a cohort comparison study with a larger cohort of dyads is needed to establish treatment efficacy.

Accessibility and Applicability of Currently Available e-Mental Health Programs for Depression for People With Poststroke Aphasia: Scoping Review.

BACKGROUND: Depression affects approximately 60% of people with aphasia 1 year post stroke and is associated with disability, lower quality of life, and mortality. Web-delivered mental health (e-mental health) programs are effective, convenient, and cost-effective for the general population and thus are increasingly used in the management of depression. However, it is unknown if such services are applicable and communicatively accessible to people with poststroke aphasia. OBJECTIVE: The aim of this study was to identify freely available e-mental health programs for depression and determine their applicability and accessibility for people with poststroke aphasia. METHODS: A Web-based search was conducted to identify and review freely available e-mental health programs for depression. These programs were then evaluated in terms of their (1) general features via a general evaluation tool, (2) communicative accessibility for people with aphasia via an aphasia-specific communicative accessibility evaluation tool, and (3) empirical evidence for the general population and stroke survivors with and without aphasia. The program that met the most general evaluation criteria and aphasia-specific communicative accessibility evaluation criteria was then trialed by a small subgroup of people with poststroke aphasia. RESULTS: A total of 8 programs were identified. Of these, 4 had published evidence in support of their efficacy for use within the general population. However, no empirical evidence was identified that specifically supported any programs' use for stroke survivors with or without aphasia. One evidence-based program scored at least 80% (16/19 and 16/20, respectively) on both the general and aphasia-specific communicative accessibility evaluation tools and was subject to a preliminary trial by 3 people with poststroke aphasia. During this trial, participants were either unable to independently use the program or gave it low usability scores on a post-trial satisfaction survey. On this basis, further evaluation was considered unwarranted. CONCLUSIONS: Despite fulfilling majority of the general evaluation and aphasia-specific evaluation criteria, the highest rated program was still found to be unsuitable for people with poststroke aphasia. Thus, e-mental health programs require substantial redevelopment if they are likely to be useful to people with poststroke aphasia.

Construction of a highly thermostable 1,3-1,4-ß-glucanase by combinational mutagenesis and its potential application in the brewing industry.

OBJECTIVES: To improve the thermostability and catalytic property of a mesophilic 1,3-1,4-ß-glucanase by combinational mutagenesis and to test its effect in congress mashing. RESULTS: A mutant ß-glucanase (rE-BglTO) constructed by combinational mutagenesis showed a 25 °C increase in optimal temperature (to 70 °C) a 19.5 °C rise in T 50 value and a 15.6 °C increase in melting temperature compared to wild-type enzyme. Its half-life values at 60 and 70 °C were 152 and 99 min, which were 370 and 800 % higher than those of wild-type enzyme. Besides, its specific activity and k cat value were 42,734 U mg-1 and 189 s-1 while its stability under acidic conditions was also improved. In flask fermentation, the catalytic activity of rE-BglTO reached 2381 U ml-1, which was 63 % higher than that of wild-type enzyme. The addition of rE-BglTO in congress mashing decreased the filtration time and viscosity by 21.3 and 9.6 %, respectively. CONCLUSIONS: The mutant ß-glucanase showed high catalytic activity and thermostability which indicated that rE-BglTO is a good candidate for application in the brewing industry.

Refining an Asynchronous Telerehabilitation Platform for Speech-Language Pathology: Engaging End-Users in the Process.

Asynchronous telerehabilitation in which computer-based interventions are remotely monitored and adapted offline is an emerging service delivery model in the rehabilitation of communication disorders. The asynchronous nature of this model may hold a benefit over its synchronous counterpart by eliminating scheduling issues and thus improving efficiency in a healthcare landscape of constrained resource allocation. The design of asynchronous telerehabilitation platforms should therefore ensure efficiency and flexibility. The authors have been engaged in a program of research to develop and evaluate an asynchronous telerehabilitation platform for use in speech-language pathology. eSALT is a novel asynchronous telerehabilitation platform in which clinicians design and individualize therapy tasks for transfer to a client's mobile device. An inbuilt telerehabilitation module allows for remote monitoring and updating of tasks. This paper introduces eSALT and reports outcomes from an usability study that considered the needs of two end-user groups, people with aphasia and clinicians, in the on-going refinement of eSALT. In the study participants with aphasia were paired with clinicians who used eSALT to design and customize therapy tasks. After training on the mobile device the participants engaged in therapy at home for a period of 3 weeks, while clinicians remotely monitored and updated tasks. Following the home trial, participants, and clinicians engaged in semi-structured interviews and completed surveys on the usability of eSALT and their satisfaction with the platform. Content analysis of data involving five participants and three clinicians revealed a number of usability themes including ease of use, user support, satisfaction, limitations, and potential improvements. These findings were translated into a number of refinements of the eSALT platform including the development of a client interface for use on the Apple iPad®, greater variety in feedback options to both the participant and clinician, automatic transfer of results to the clinician, and expansion of the task template list. This research highlights the importance of including end-users in the process of technology refinement, in order to ensure effective and efficient use of the technology. Future directions for research are discussed including clinical trials in which the effectiveness of and adherence to intervention protocols using asynchronous telerehabilitation are examined.

Novel nonmajor histocompatibility complex-linked loci from mouse chromosome 17 confer susceptibility to viral-mediated chronic autoimmune myocarditis.

BACKGROUND: Development of viral-induced chronic myocarditis is thought to involve both environmental and genetic factors. However, to date, no susceptibility genes have been identified. METHODS AND RESULTS: We sought to identify loci that confer susceptibility to viral-induced chronic myocarditis with the use of chromosome substitution strain mice that are composed of 1 chromosome from the disease susceptible A/J strain on an otherwise resistant C57BL/6 background. By this method, we identified chromosome 17 to confer susceptibility. To further isolate the region of susceptibility, 8 strains of mice congenic for different portions of chromosome 17 were generated. Characterization of these strains identified at least 4 susceptibility loci on the chromosome. Three of these loci are located in the proximal 22.8 cM, whereas the fourth locus is located in the portion of the chromosome distal to 34.3 cM. CONCLUSIONS: We have identified 4 loci that confer susceptibility of viral-induced chronic myocarditis. Of these loci, 3 were distinct from the major histocompatibility complex locus and thus represent novel susceptibility loci. The close proximately of the 2 novel loci with susceptibility loci for other autoimmune diseases such as type 1 diabetes and chronic experimental autoimmune thyroiditis suggests the presence of global autoimmune susceptibility genes.

Genetic resistance to diet-induced obesity in chromosome substitution strains of mice.

Discovery of genes that confer resistance to diseases such as diet-induced obesity could have tremendous therapeutic impact. We previously demonstrated that the C57BL/6J-Chr(A/J)/NaJ panel of chromosome substitution strains (CSSs) is a unique model for studying resistance to diet-induced obesity. In the present study, three replicate CSS surveys showed remarkable consistency, with 13 A/J-derived chromosomes reproducibly conferring resistance to high-fat-diet-induced obesity. Twenty CSS intercrosses, one derived from each of the 19 autosomes and chromosome X, were used to determine the number and location of quantitative trait loci (QTLs) on individual chromosomes and localized six QTLs. However, analyses of mean body weight in intercross progeny versus C57BL/6J provided strong evidence that many QTLs discovered in the CSS surveys eluded detection in these CSS intercrosses. Studies of the temporal effects of these QTLs suggest that obesity resistance was dynamic, with QTLs acting at different ages or after different durations of diet exposure. Thus, these studies provide insight into the genetic architecture of complex traits such as resistance to diet-induced obesity in the C57BL/6J-Chr(A/J)/NaJ CSSs. Because some of the QTLs detected in the CSS intercrosses were not detected using a traditional C57BL/6J x A/J intercross, our results demonstrate that surveys of CSSs and congenic strains derived from them are useful complementary tools for analyzing complex traits.

Genetic architecture of complex traits: large phenotypic effects and pervasive epistasis.

The genetic architecture of complex traits underlying physiology and disease in most organisms remains elusive. We still know little about the number of genes that underlie these traits, the magnitude of their effects, or the extent to which they interact. Chromosome substitution strains (CSSs) enable statistically powerful studies based on testing engineered inbred strains that have single, unique, and nonoverlapping genetic differences, thereby providing measures of phenotypic effects that are attributable to individual chromosomes. Here, we report a study of phenotypic effects and gene interactions for 90 blood, bone, and metabolic traits in a mouse CSS panel and 54 traits in a rat CSS panel. Two key observations emerge about the genetic architecture of these traits. First, the traits tend to be highly polygenic: across the genome, many individual chromosome substitutions each had significant phenotypic effects and, within each of the chromosomes studied, multiple distinct loci were found. Second, strong epistasis was found among the individual chromosomes. Specifically, individual chromosome substitutions often conferred surprisingly large effects (often a substantial fraction of the entire phenotypic difference between the parental strains), with the result that the sum of these individual effects often dramatically exceeded the difference between the parental strains. We suggest that strong, pervasive epistasis may reflect the presence of several phenotypically-buffered physiological states. These results have implications for identification of complex trait genes, developmental and physiological studies of phenotypic variation, and opportunities to engineer phenotypic outcomes in complex biological systems.

Quantitative trait locus analysis for hemostasis and thrombosis.

Susceptibility to thrombosis varies in human populations as well as many in inbred mouse strains. The objective of this study was to characterize the genetic control of thrombotic risk on three chromosomes. Previously, utilizing a tail-bleeding/rebleeding assay as a surrogate of hemostasis and thrombosis function, three mouse chromosome substitution strains (CSS) (B6-Chr5(A/J), Chr11(A/J), Chr17(A/J)) were identified (Hmtb1, Hmtb2, Hmtb3). The tail-bleeding/rebleeding assay is widely used and distinguishes mice with genetic defects in blood clot formation or dissolution. In the present study, quantitative trait locus (QTL) analysis revealed a significant locus for rebleeding (clot stability) time (time between cessation of initial bleeding and start of the second bleeding) on chromosome 5, suggestive loci for bleeding time (time between start of bleeding and cessation of bleeding) also on chromosomes 5, and two suggestive loci for clot stability on chromosome 17 and one on chromosome 11. The three CSS and the parent A/J had elevated clot stability time. There was no interaction of genes on chromosome 11 with genes on chromosome 5 or chromosome 17. On chromosome 17, twenty-three candidate genes were identified in synteny with previously identified loci for thrombotic risk on human chromosome 18. Thus, we have identified new QTLs and candidate genes not previously known to influence thrombotic risk.

Resistance to diet-induced obesity in mice with a single substituted chromosome.

Obesity and its comorbidities are taking an increasing toll on human health. Key pathways that were identified with single gene variants in humans and model organisms have led to improved understanding and treatment of rare cases of human obesity. However, similar progress remains elusive for the more common multifactorial cases of metabolic dysfunction and disease. A survey of mouse chromosome substitution strains (CSSs) provided insight into the complex genetic control of diet-induced obesity and related conditions. We now report a survey of 60 traits related to obesity and metabolic syndrome in mice with a single substituted chromosome as well as selected traits measured in congenic strains derived from the substituted strain. We found that each strain that was resistant to diet-induced obesity had a distinct phenotype that uniquely modeled different combinations of traits related to metabolic disease. For example, the chromosome 6 CSS remained insulin resistant in the absence of obesity, demonstrating an atypical relationship between body weight and insulin resistance. These results provide insights into the genetic control of constant components of this mouse model of diet-induced metabolic disease as well as phenotypes that vary depending on genetic background. A better understanding of these genotype-phenotype relationships may enable a more individualized diagnosis and treatment of obesity and the metabolic syndrome.