Impact of integrated translational research on clinical exome sequencing.

PURPOSE: Exome sequencing often identifies pathogenic genetic variants in patients with undiagnosed diseases. Nevertheless, frequent findings of variants of uncertain significance necessitate additional efforts to establish causality before reaching a conclusive diagnosis. To provide comprehensive genomic testing to patients with undiagnosed disease, we established an Individualized Medicine Clinic, which offered clinical exome testing and included a Translational Omics Program (TOP) that provided variant curation, research activities, or research exome sequencing. METHODS: From 2012 to 2018, 1101 unselected patients with undiagnosed diseases received exome testing. Outcomes were reviewed to assess impact of the TOP and patient characteristics on diagnostic rates through descriptive and multivariate analyses. RESULTS: The overall diagnostic yield was 24.9% (274 of 1101 patients), with 174 (15.8% of 1101) diagnosed on the basis of clinical exome sequencing alone. Four hundred twenty-three patients with nondiagnostic or without access to clinical exome sequencing were evaluated by the TOP, with 100 (9% of 1101) patients receiving a diagnosis, accounting for 36.5% of the diagnostic yield. The identification of a genetic diagnosis was influenced by the age at time of testing and the disease phenotype of the patient. CONCLUSION: Integration of translational research activities into clinical practice of a tertiary medical center can significantly increase the diagnostic yield of patients with undiagnosed disease.

Switching the World's Salt Supply-Learning from Iodization to Achieve Potassium Enrichment.

Sodium is an essential dietary component, but excess sodium intake can lead to high blood pressure and an increased risk of cardiovascular disease. Many national and international bodies, including the World Health Organization, have advocated for population-wide sodium reduction interventions. Most have been unsuccessful due to inadequate sodium reduction by food industry and difficulties in persuading consumers to add less salt to food. Recent research highlights potassium-enriched salt as a new, feasible, acceptable, and scalable approach to reducing the harms caused by excess sodium and inadequate potassium consumption. Modeling shows that a global switch from regular salt to potassium-enriched salt has the potential to avert millions of strokes, heart attacks, and premature deaths worldwide each year. There will be many challenges in switching the world's salt supply to potassium-enriched salt, but the success of universal salt iodization shows that making a global change to the manufacture and use of salt is a tractable proposition. This in-depth review of universal salt iodization identified the importance of a multisectoral effort with strong global leadership, the support of multilateral organizations, engagement with the salt industry, empowered incountry teams, strong participation of national governments, understanding the salt supply chain, and a strategic advocacy and communication plan. Key challenges to the implementation of the iodization program were costs to government, industry, and consumers, industry concerns about consumer acceptability, variance in the size and capabilities of salt producers, inconsistent quality control, ineffective regulation, and trade-related regulatory issues. Many of the opportunities and challenges to universal salt iodization will likely also be applicable to switching the global salt supply to iodized and potassium-enriched salt.

Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2.

OBJECTIVE: We describe the clinical characteristics and genetic etiology of several new cases within the ACO2-related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear-encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice-site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities. METHODS: We describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature. RESULTS: Two siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy-like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months. INTERPRETATION: In this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.

Have broad-based community and professional education programs influenced mental health literacy and treatment seeking of those with major depression and suicidal ideation?

Mental health literacy is the knowledge and beliefs about mental disorders that aid in their recognition, management, or prevention; it is also a determinant of help seeking. As such, it is presumed to be important in community suicide prevention programs. In Australia there have been a number of government, professional, and charitable organizations as well as pharmaceutical company suicide prevention initiatives which have been designed to enhance public and professional knowledge about mental disorders, particularly depression. This naturalistic study conducted between 1998 and 2004 in a random and representative population sample examined the changes in mental health literacy and treatment seeking of those with major depression, both with and without suicidal ideation, and those who were neither depressed nor suicidal. Results indicated that there was marked improvement in mental health literacy for all three groups, although there was less change for those most in need of intervention (i.e., those with major depression and suicidal ideation). Furthermore, there were fewer changes in appropriate treatment seeking in those with major depression and suicidal ideation. These findings are consistent with literature reporting limited problem solving and decision making in those who are suicidal, and indicate that there are limits to broadbased community education programs. More focused suicide prevention initiatives are required, specifically for those who are depressed and suicidal.

Diabetes, depression, and quality of life: a population study.

OBJECTIVE: The aim of the study was to assess the prevalence of diabetes and depression and their associations with quality of life using a representative population sample. RESEARCH DESIGN AND METHODS: The study consisted of a representative population sample of individuals aged > or = 15 years living in South Australia comprising 3,010 personal interviews conducted by trained health interviewers. The prevalence of depression in those suffering doctor-diagnosed diabetes and comparative effects of diabetic status and depression on quality-of-life dimensions were measured. RESULTS: The prevalence of depression in the diabetic population was 24% compared with 17% in the nondiabetic population. Those with diabetes and depression experienced an impact with a large effect size on every dimension of the Short Form Health-Related Quality-of-Life Questionnaire (SF-36) as compared with those who suffered diabetes and who were not depressed. A supplementary analysis comparing both depressed diabetic and depressed nondiabetic groups showed there were statistically significant differences in the quality-of-life effects between the two depressed populations in the physical and mental component summaries of the SF-36. CONCLUSIONS: Depression for those with diabetes is an important comorbidity that requires careful management because of its severe impact on quality of life.

Is there a relationship between Wolfram syndrome carrier status and suicide?

Wolfram syndrome (WFS) is a rare, autosomal recessive neurodegenerative disorder. An increased risk of psychiatric disorders and suicide has been reported for heterozygote carriers. In this study we investigated whether mutations in the WFS gene are associated with suicide in the general population. The gene for WFS (WFS1) has recently been mapped to chromosome 4p16.1, and its genomic structure has been characterized. We screened the entire WFS1 ORF in a panel of 100 completed suicides, 60 blood donors not known to have psychiatric illness, and 100 donors with a negative history of depression or suicidal behavior. We did not find evidence of an increased incidence of WFS carriers in the suicide panel and concluded that WFS1 carrier status is not a significant contributor to suicide in the general population. Screening of this highly polymorphic gene resulted in the detection of 33 variants, 13 of which cause amino acid changes. Seven of these changes have not been previously reported and six were unique to our suicide panel.

Population attributable risk of major depression for suicidal ideation in a random and representative community sample.

BACKGROUND: The importance of depression in suicidal behaviour and suicidal ideation is usually determined on clinical samples. However, public health planning also requires population data. This study utilised the population attributable risk statistic in determining the importance of major depression as a contributing factor to suicidal ideation in a random and representative sample of the population. METHOD: Major depression and suicidal ideation as well as demographic and clinical data were delineated in a random and representative population sample of 3010 subjects. The population attributable risk statistic was used to determine the contribution of major depression to suicidal ideation. RESULTS: Multivariate analysis demonstrated that major depression was the major contributor to the risk for suicidal ideation with a population attributable risk of 56.6%. CONCLUSIONS: These results, utilising different measures of depression and suicidal ideation to those few previous population attributable risk studies examining this issue, confirm the overwhelming importance of major depression as a contributing factor to suicidal ideation in the community.

Mental health literacy of those with major depression and suicidal ideation: an impediment to help seeking.

Mental health literacy is the knowledge and beliefs about mental disorders that aid their recognition, management, or prevention, and is an important determinant of help seeking. This has relevance in suicide prevention, particularly for those with major depression, the clinical condition most frequently associated with suicidal behavior. In this study of a random and representative community sample, a vignette depicting classical features of major depression was presented to subjects along with questions related to mental health literacy. The responses of those with major depression, as delineated by the Primary Care Evaluation of Mental Disorders instrument, both with and without suicidal ideation, were compared to those of a third group of respondents. The results demonstrated that despite increased professional contact by those with major depression and suicidal ideation, there were few differences among the three groups on either open-ended or direct questions related to mental health literacy. This indicates that increased professional contact in itself was not related to increased mental health literacy, and suggests that more specific psychoeducational programs are required.

Bipolar disorders in Australia. A population-based study of excess costs.

OBJECTIVE: To estimate the excess costs associated with bipolar disorders in Australia, based on prevalence (using the Mood Disorder Questionnaire (MDQ)) and associated excess burden-of-illness costs. METHODS: Using data from the 2004 South Australian Health Omnibus Survey (HOS), a weighted cross-sectional survey of 3,015 adults, excess costs were estimated from health service utilisation. RESULTS: There was a 2.5% lifetime prevalence of bipolar disorders, delineated by the MDQ. Those persons (MDQ positive) reported a significantly greater use of services and a poorer health status and quality of life than those who were MDQ negative. Using the service provision perspective, excess costs of bipolar disorders in Australia were approx $3.97-$4.95 billion. CONCLUSIONS: These results from an Australian population demonstrate the significant economic burden of bipolar disorders. Our findings emphasise the need for further evaluation of the cost-effectiveness of different treatments, or alternative means of reducing the burden borne by individuals, the health system and the general community.

Have education and publicity about depression made a difference? Comparison of prevalence, service use and excess costs in South Australia: 1998 and 2004.

OBJECTIVE: To identify changes in depression, its management and associated excess costs, between 1998 and 2004 in South Australia. METHODS: A face-to-face Health Omnibus Survey was conducted in 2004 among 3015 randomly selected participants aged 15 years and over, who were a random and representative sample of the South Australian population, and this was compared with a survey conducted in 1998 that used the same methodology. The main outcome measures were prevalence of depression detected by the Mood Module of the Primary Care Evaluation of Mental Disorders (PRIME-MD); use of health services; health-related quality of life assessed by the Assessment of Quality of Life; estimates of excess costs and demographic data. RESULTS: There was no significant change in the overall prevalence of depression, although there was a significant decrease in respondents with other depressions, and a non-significant increase in those with major depression. No significant differences in the mean number of PRIME-MD depression symptoms were reported. Greater use of predominantly non-medical treatment services and antidepressants were reported by both those with depression and those without depression. There was a marked increase in the associated excess costs of depression. CONCLUSIONS: There has been no significant improvement in the prevalence of depression and its associated morbidity and financial burden in the South Australian community between 1998 and 2004, despite a number of professional and community education programmes. It is possible that without these efforts and the increased treatment reported on in this survey, there may have been an increase in the prevalence of depression and an even greater financial burden. However, it is also possible that community services for the provision of treatment for depression have not been able to implement research strategies that have been demonstrated to be effective.

Use of prescribed medications in a South Australian community sample.

OBJECTIVE: To determine the extent of self-reported use of prescription medications in an Australian community sample. DESIGN, SETTING AND PARTICIPANTS: Face-to-face interviews with a random, representative sample of the South Australian population (aged > or = 15 years) living in metropolitan and rural areas. The study, a Health Omnibus Survey, was conducted between March and June 2004. MAIN OUTCOME MEASURES: Reported number of prescribed medications used per person, most common categories of medication, and use by individuals of multiple medications for the same body system. RESULTS: From 4700 households selected, 3015 participants were interviewed (65.9% response rate). Of respondents, 46.8% were using prescribed medications; 171 respondents (5.7%) were taking six or more medications, and four were taking 16 or more; 23.2% were using medications for the cardiovascular system, with 11.9% using agents acting on the renin-angiotensin system. Prescription medication use increased with age, with over 10% of respondents aged > or = 55 years using six or more medications. CONCLUSIONS: Use of multiple prescribed medications was common, with the potential for significant drug interactions. Assuming a similar pattern of medication use Australia-wide, reducing the number of prescribed medications by one for people taking six or more medications would save the federal government about 380 million dollars a year.

Changes in mental health literacy about depression: South Australia, 1998 to 2004.

OBJECTIVE: To identify changes in mental health literacy in regard to depression between 1998 and 2004. DESIGN AND SETTING: Face-to-face interviews with a random and representative sample of the South Australian population in 2004, compared with a similarly conducted survey in 1998 that used the same vignette, questions and methodology. PARTICIPANTS: 3015 randomly selected participants, aged 15 years and over. MAIN OUTCOME MEASURES: Responses to both open-ended and direct questions about symptoms and treatment options for depression. RESULTS: The 3015 interviews conducted represented a response rate of 65.9%. Compared with 1998, in 2004 there was a significant increase in the proportion of people recognising depression in the vignette, acknowledging personal experience of depression, and perceiving professional assistance to be more helpful and less harmful. However, although more people nominated psychiatrists or psychologists as therapists of choice, the difference between 1998 and 2004 was not significant. CONCLUSIONS: There has been a significant increase in mental health literacy, at least as regards depression, in the South Australian community between 1998 and 2004. The lack of significant change in psychiatrists and/or psychologists being perceived as therapists of choice is of concern and suggests that community education about their expertise may be appropriate.

Bipolar I and II disorders in a random and representative Australian population.

OBJECTIVE: To assess the prevalence of bipolar I and II disorders in an Australian population. METHOD: The Mood Disorder Questionnaire (MDQ) was administered to 3015 respondents in a random and representative sample in South Australia. Health status, quality of life and demographic data were also collected. RESULTS: There was a 2.5% lifetime prevalence of bipolar I and II disorders delineated by the MDQ. Those people had a significantly greater use of services and a poorer health status and quality of life than those who were MDQ-negative. CONCLUSIONS: These results in an Australian population are consistent with other international studies showing a greater prevalence of bipolar disorders than hitherto appreciated.

Double depression in an Australian population.

BACKGROUND: Double depression, or dysthymia with superimposed major depression, is a major public health issue that imposes considerable burden on the community. Double depression and its associated morbidity have not previously been delineated in an Australian population. METHODS: A random and representative sample of the South Australian population was assessed by trained interviewers. The mood module of the Primary Care Evaluation of Mental Disorders (PRIME-MD), the Short-Form Health Status Questionnaire (SF-36), and Assessment of Quality of Life (AQoL) instruments were administered, and data related to treatment use and role functioning were collated. RESULTS: Double depression was present in 2.2% of the population. This group reported high levels of treatment-seeking behaviour with 90% seeking treatment in the last month and 42.4 % taking antidepressants. They also had a highly significantly poorer quality of life than did others in the community. CONCLUSIONS: The 2.2% of the population with double depression reported high use of services with poor functioning and health-related quality of life. More effective intervention strategies are required.

Differences in community mental health literacy in older and younger Australians.

BACKGROUND: Depression has been traditionally considered to increase with age, although that may be due to sampling of those who have presented with depressive conditions. It is now recognised that patients' understanding of depression and beliefs about its appropriate treatment, mental health literacy, influences treatment-seeking behaviour. OBJECTIVES: This study delineates depression, recent use of health services and mental health literacy in a random and representative community sample of younger and older South Australians. METHODS: Depression, health service utilisation and mental health literacy were assessed in a random and representative sample of 2010 South Australians. Results for those aged between 65 and 74 years (n=300) and those aged 15 to 24 years (n=521) were compared. RESULTS: Compared with the younger group, older subjects did not report greater levels of current depression although they were more likely to have seen a medical practitioner in the last 12 months and be taking antidepressants. However, their mental health literacy in terms of recognition of a mental health problem in a vignette was somewhat poorer and fewer recommended treatment from a counsellor, telephone service or psychologist and more considered that a psychiatrist would be harmful. They also more often perceived the clergy as helpful. CONCLUSIONS: Depression was not more common among older than younger members of the community. Despite recognising depression in a vignette less often and perceiving less likelihood of help from several different mental health professionals, those in the older group were more likely to receive antidepressant medication and to have recently consulted a medical practitioner.

Subsyndromal depression: prevalence, use of health services and quality of life in an Australian population.

BACKGROUND: A study of the prevalence, use of services and quality of life of those with subsyndromal depression in a random and representative Australian population. METHODS: A face-to-face Health Omnibus survey of 3010 respondents administered the mood module of the PRIME-MD and the SF-36 and AQoL quality of life instruments. RESULTS: Subsyndromal depressive symptoms were identified in 12.9% of respondents. There was a gradation of use of services from those with no depression, to those with subsyndromal, other and major depressions. Those with subsyndromal depression scored significantly worse on quality of life measures than those with no depression, but the effect size was small and less than the poorer functioning of those with other depressive syndromes, particularly major depression. CONCLUSIONS: Subsyndromal depression is very prevalent in the community and worthy of clinical consideration.

Asthma symptoms associated with depression and lower quality of life: a population survey.

OBJECTIVE: To identify any association between asthma and depression and quality of life. DESIGN AND SETTING: A face-to-face Health Omnibus Survey of a random and representative sample of the South Australian population in August 1998. PARTICIPANTS: 3010 randomly selected participants aged 15 years and over. MAIN OUTCOME MEASURES: Prevalence of doctor-diagnosed asthma, and scores for depression (measured by PRIME-MD instrument) and quality of life (measured by SF-36) in affected participants. RESULTS: The prevalence of asthma was 9.9%. The prevalence of major depression was significantly higher for those who experienced dyspnoea, wakening at night with asthma, and morning symptoms of asthma. Quality-of-life scores were also lower for the same groups. CONCLUSIONS: Depression is a serious but potentially remediable comorbidity with asthma that may affect appropriate diagnosis and outcome.

Electroconvulsive therapy, depression, and cognitive outcomes: an Australian audit.

OBJECTIVES: We sought to compare cognitive and other outcomes of 2 groups of mood disorder patients, those who received ECT and those who did not, from 2 private South Australian hospitals during a 12-month period. METHODS: Patients were assessed at admission and discharge from hospital on 2 validated instruments: the Health of the Nation Outcome Scales (HoNOS) and an abbreviated version of the Short-Form 36-item Health Status Questionnaire (SF-36). RESULTS: Patient scores on the majority of subscales of both the HoNOS and SF-36 indicated a positive response to either ECT or non-ECT. There was no significant difference in HoNOS depression score between the ECT and non-ECT groups upon discharge, despite the ECT group being significantly more depressed at admission. Cognitive functioning of those who received ECT did not change significantly from admission to discharge. However, they did not share the significant improvement in cognitive functioning of those depressed persons who had non-ECT treatment. CONCLUSIONS: ECT treatment of depression was not associated with a deterioration of cognitive functioning.