| 1. |
- Allesøe, Rosa Lundbye, et al.
(author)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Journal article (peer-reviewed)abstract
- The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug–omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug–drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
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| 2. |
- Guintivano, Jerry, et al.
(author)
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Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression
- 2023
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In: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 180:12, s. 884-895
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
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| 3. |
- Koivula, Robert, et al.
(author)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : rationale and design of the epidemiological studies within the IMI DIRECT Consortium
- 2014
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 57:6, s. 1132-1142
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS:The DIRECT (Diabetes Research on Patient Stratification) Study is part of a European Union Framework 7 Innovative Medicines Initiative project, a joint undertaking between four industry and 21 academic partners throughout Europe. The Consortium aims to discover and validate biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper describes two new prospective cohort studies conducted as part of DIRECT.METHODS:Prediabetic participants (target sample size 2,200-2,700) and patients with newly diagnosed type 2 diabetes (target sample size ~1,000) are undergoing detailed metabolic phenotyping at baseline and 18 months and 36 months later. Abdominal, pancreatic and liver fat is assessed using MRI. Insulin secretion and action are assessed using frequently sampled OGTTs in non-diabetic participants, and frequently sampled mixed-meal tolerance tests in patients with type 2 diabetes. Biosamples include venous blood, faeces, urine and nail clippings, which, among other biochemical analyses, will be characterised at genetic, transcriptomic, metabolomic, proteomic and metagenomic levels. Lifestyle is assessed using high-resolution triaxial accelerometry, 24 h diet record, and food habit questionnaires.CONCLUSIONS/INTERPRETATION:DIRECT will yield an unprecedented array of biomaterials and data. This resource, available through managed access to scientists within and outside the Consortium, will facilitate the development of new treatments and therapeutic strategies for the prevention and management of type 2 diabetes
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| 4. |
- Koivula, Robert W., et al.
(author)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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In: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
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Journal article (peer-reviewed)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 5. |
- Lee, K S Kylie, et al.
(author)
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Developing a tablet computer-based application ('App') to measure self-reported alcohol consumption in Indigenous Australians
- 2018
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In: BMC Medical Informatics and Decision Making. - : Springer Science and Business Media LLC. - 1472-6947. ; 18:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: The challenges of assessing alcohol consumption can be greater in Indigenous communities where there may be culturally distinct approaches to communication, sharing of drinking containers and episodic patterns of drinking. This paper discusses the processes used to develop a tablet computer-based application ('App') to collect a detailed assessment of drinking patterns in Indigenous Australians. The key features of the resulting App are described.METHODS: An iterative consultation process was used (instead of one-off focus groups), with Indigenous cultural experts and clinical experts. Regular (weekly or more) advice was sought over a 12-month period from Indigenous community leaders and from a range of Indigenous and non-Indigenous health professionals and researchers.RESULTS: The underpinning principles, selected survey items, and key technical features of the App are described. Features include culturally appropriate questioning style and gender-specific voice and images; community-recognised events used as reference points to 'anchor' time periods; 'translation' to colloquial English and (for audio) to traditional language; interactive visual approaches to estimate quantity of drinking; images of specific brands of alcohol, rather than abstract description of alcohol type (e.g. 'spirits'); images of make-shift drinking containers; option to estimate consumption based on the individual's share of what the group drank.CONCLUSIONS: With any survey platform, helping participants to accurately reflect on and report their drinking presents a challenge. The availability of interactive, tablet-based technologies enables potential bridging of differences in culture and lifestyle and enhanced reporting.
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| 6. |
- Weatherall, Teagan J., et al.
(author)
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Alcohol dependence in a community sample of Aboriginal and Torres Strait Islander Australians : harms, getting help and awareness of local treatments
- 2021
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In: Addiction science & clinical practice. - : Springer Science and Business Media LLC. - 1940-0632 .- 1940-0640. ; 16:1
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Journal article (peer-reviewed)abstract
- Background: Few studies have examined links between current alcohol dependence and specific harms among Indigenous Australians. We investigated these associations as well as help seeking for drinking, awareness of local treatments and recommendations to help family or friends cut down or stop drinking in two Indigenous communities.Methods: A representative sample of Indigenous Australians was surveyed in one urban and one remote community in South Australia. Data were collected via the Grog Survey App. Participants were dependent if they reported two or more symptoms of alcohol dependence (ICD-11). Pearson chi-square tests were used to describe relationships between employment by gender, and dependence by awareness of medicines and local treatment options. Multivariate logistic regressions were used to predict the odds of dependent drinkers experiencing harms and getting help for drinking, controlling for age, gender, schooling and income.Results: A total of 775 Indigenous Australians took part in the study. After controlling for confounders, dependent drinkers were nearly eight times more likely to report a harm and nearly three times more likely to get help for their drinking—compared with non-dependent drinkers. Participants recommended accessing local support from an Aboriginal alcohol and other drugs worker, or a detoxification/ rehabilitation service.Discussion and conclusions: More support and funding is needed for Indigenous Australians to ensure local treatment options for dependent drinkers are readily available, appropriate and accessible. Involvement of local Aboriginal or Torres Strait Islander health professionals in delivery of care can help ensure that it is appropriate to an individual’s culture and context.
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| 7. |
- Weatherall, Teagan J., et al.
(author)
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Prevalence and correlates of alcohol dependence in an Australian Aboriginal and Torres Strait Islander representative sample : Using the Grog Survey App
- 2022
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In: Drug and Alcohol Review. - : Wiley. - 0959-5236 .- 1465-3362. ; 41:1, s. 125-134
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Journal article (peer-reviewed)abstract
- Introduction. Little is known about the prevalence of current alcohol dependence in Indigenous Australian communities. Here we identify the frequency of reported symptoms, estimate the prevalence and describe the correlates of current alcohol dependence. Methods. A representative sample of Indigenous Australians (16+ years) was recruited from an urban and remote community in South Australia. Data were collected between July and October 2019 via a tablet computer-based application. Participants were likely dependent if they reported two or more dependence symptoms (ICD-11; in the last 12 -months), weekly or more frequently. Chi-square tests described the relationship between demographics, remoteness and alcohol dependence. Spearman correlations estimated the relationship between symptoms of dependence, consumption characteristics and demographics. Results. A total of 775 Indigenous Australians participated. The most frequently reported symptoms were prioritising alcohol over other things and loss of control. Overall, 2.2% were likely dependent on alcohol (n = 17/775). Prevalence did not vary by remoteness. Participants who drank more and more frequently tended to report more frequent symptoms of dependence. In the urban site, men tended to report more frequent symptoms of dependence than women. Age, income and schooling were not linked to dependence. Discussion and Conclusions. The prevalence of current alcohol dependence in this representative sample was similar to that of the general Australian and international estimates. Understanding risk factors for current alcohol dependence will be useful to inform the allocation of funding and support. Accurate estimates of the prevalence of current alcohol dependence are important to better identify specialist treatment needs.
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