BDMM onset time dependence. BDMM of depression and metabolic disorders and hypertension. S5 Fig. The high posteriors in the full analysis, and their sharp decrease in the restricted analysis may indicate that these disorders are heterogeneous themselves: in some subgroups of disorder the symptoms are part of the depression phenotype with high biological overlap but other subgroups maybe independent of depression or adversities that non-specifically predispose to depression.
Discussion Large-scale cohort studies collecting life style, environmental, physiological, clinical and molecular level data, provide unprecedented opportunity for understanding health, pre-disease states, multimorbid conditions and progressions, especially to use epidemilogical level information to complement molecular level discoveries [ 238 — 1347 ].
However, the hypothesis-free, omic level use of comorbidites is hindered by multiple factors, such as by errors and biases in disease coding and collection of clinical information and by confounders like therapies, drug consumption or paradoxically the shared genetic factors themselves.
A further imminent challenge is the presence of disease-mediated or disease-confounded comorbidity relations, i.
In network science, algebraic solutions were proposed to attenuate indirect relations [ 19 ], but these solutions do not take into account the complex system of probabilistic dependencies between morbidities.
We proposed to use probabilistic graphical models, specifically Bayesian networks to discriminate direct and indirect relations, because their semantics perfectly captures this aspect [ 434849 ].
Indeed, the exact probabilistic treatment of a direct relation with respect to a given set of variables relies on the practical assumption of stability [ 4850 ], less demanding than assumptions for a causal interpretation [ 51 ]. Additionally, we examined the comorbidity relations of psychiatric and metabolic disorders, specifically for depression in BDMMs.
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In Fig 6 we further evaluated the connections with significant Bonferroni-corrected χ2 p-values but below the 0. This shows that most of these connections have high BDMM structural association posterior, which suggest that BDMM indeed filtered mediated and confounded relations. These disorder pairs rarely occur together in patients mean co-occurrence For detailed description of the molecular level methods and results see S1 Appendix and [ 216 ]. Our results showed another expected aspect, namely that this relationship is independent of the order of the onset of these disorders.
This observation is in line with a longitudinal study which showed that generalised anxiety disorder GAD and major depressive disorder MDD are strongly comorbid with an equal probability of GAD or MDD occurring first or simultaneously suggesting they might not be distinct disorders [ 54 ].
Although overlapping genetic risk factors for anxiety and depression have not yet been identified, common genetic vulnerability has been found for other comorbid psychiatric disorders [ 323355 ]. Multimorbidity pattern of metabolic disorders and hypertension british medical journal type 2 diabetes depression Epidemiologic studies repeatedly report high comorbidity between depression and metabolic disorders [ 57 ], depression and diabetes [ 58 ], depression and cardiovascular disorders [ 37 ], depression and hypertension [ 5960 ], and diabetes mellitus 1 fórum kezelése and obesity [ 6162 ].
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However, there have been several contradictory results, and this suggests a more complex relationship. Indeed, recent GWAS results found no shared genetic risk between these disorders and depression [ 55 ].
When we excluded occurrences after the onset of depression the direct relationship between obesity and depression remained as expected but entirely new links with high posterior probability emerged suggesting a strong relationship between the consequences of metabolic syndromes and depression.
Studies of the genetic relationship between obesity and depression suggest that atypical depression, characterised by increase in appetite and weight, is associated with genetic risk factors and polygenic risk scores of increased BMI and triglycerides, while typical depression, with decreased appetite and weight, show more similarities with other psychiatric disorders [ 6364 ]. Thus, in line with our results comorbid obesity and metabolic disorders may identify a specific subtype of depression with a distinct biological background.
We cannot currently exclude the possibility that lifestyle factors, such as diet, physical activity and stress, or medication used to treat hypertension, hypercholesterolaemia and obesity may contribute to the later development of depression [ 65 ]. As a specific example, a previous study demonstrated that current psychological distress amplified the effect of genetic risk of high BMI [ 66 ].
Patients with increased genetic risk to become overweight showed worse physical outcome higher BMIand quite probably more comorbid psychological symptoms, when life stress was present. Furthermore, it has been reported that statins, drugs with cholesterol-lowering effect, have antidepressant effect in patients with comorbid depression and coronary artery disease while the same drugs can have pro-depressive effect or no effect on depression when comorbidities and depression subtypes were not taken into account [ 67 ].
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It is therefore puzzling that they involve different etiological mechanisms. In addition, their symptoms often overlap making it difficult to apply diagnostic categories. The probable explanation is that in general, these disorders are related to consequences of depression and only specific subtypes of these disorders can be expected to have causal relations, e.
For example, a genetic risk score analysis demonstrated that migraine with comorbid depression was more genetically related to depression than to pure migraine, which suggests that migraine might develop as a consequence of different polygenic backgrounds [ 71 ]. Limitations One of the main limitations is that all disorders were self-reported, although trained nurses evaluated and corrected all entries during face-to-face interviews.
The second one is that the applied treatments or medications were not included in the analysis which could highlight comorbidities due to the side effect of treatments.
The emergence of new drugs for IBS-D has been slow and there is a need for new treatments, including drug-free treatments, which are easy to use and suitable for different patient groups.
We will address this problem in follow-up studies. Note that we only used a subset of the UK Biobank dataset selecting those participants who filled out the Mental Health Questionnaire and provided online dietary information, which may introduce confounding through selection bias. However, limiting our study to this subpopulation enabled us to test different definitions of depression and will allow us to connect this comorbidity network to relevant environmental risk factors.
Conclusion The use of large-scale health data sets, such as the UK Biobank dataset hold the promise of complementing and guiding the molecular level research of complex diseases.
Adopting an intermediary approach between statistical association analysis and causal discovery british medical journal type 2 diabetes investigated the use of Bayesian networks in the Bayesian model averaging framework to explore direct probabilistic relations with respect to a given set of variables, i.
We demonstrated the applicability of BDMMs, especially their principled capability of discriminating direct and indirect comorbidities.
In summary, PGMs offer maximally sparse dependency models and utilize the omic nature of the epidemiologic data jointly modelling all the morbidities; while the Bayesian approach through posteriors provides an explicit representation for the uncertainties in a dataset. Thus the Bayesian direct morbidity maps provide sparse, systems-based, omic-wide perspectives. From a clinical perspective, our results also highlight that the direct and indirect subtypes of comorbidities support a finer biological interpretation, namely an interactome-based detailed interpretation using molecular mechanisms corresponding to direct relations, whereas genetic overlap using associative gene sets may only reflect indirect comorbidities.
In addition, re-running the analysis by including only instances of disorders which preceded depression, we delineated comorbid disorders of depression with more refined british medical journal type 2 diabetes roles that could specify subgroups of depressed patients with more homogenous background. The investigation of Bayesian direct morbidity maps also demonstrated, that even large-scale datasets such as UK Biobank, are still limited for non-ambiguous identification of complex dependency patterns such as multimorbidities [ 73 ].
However, the applied Bayesian statistical framework offers an automated, normative solution for the multiple hypothesis testing problem and the application of probabilistic graphical models in the Bayesian framework supports the versatile post-processing of the results and their efficient communication and sharing. The results of our research highlight the advantages of Bayesian systems-based modelling, which could be vital to cope with the growing heterogeneity of new health data sets containing full personal genetic information with high dimensional data about lifestyle, environmental factors and sequential decisions on drug therapies [ 874 ].
For statistical analysis, sex was included into the data set, and age was binned into 3 equal frequency categories with thresholds 60 and 68 years. Then we applied the different pairwise measures and logistic regression together with Bayesian systems-based modelling to compare the models computed on these datasets see below and in S1 Appendix.
To investigate the effect of disease onset, self-reported disease onset data was used to filter the dataset.
We extended the dataset with sex, age and BMI-based obesity. The data were analysed using same statistical methods as with the non-filtered dataset. To test the stability of comorbid relationships with depression we also used an alternative depression definition instead of self-reported depressive disorder.
Depression and its severity was defined by the Mental Health Questionnaire data [ 46 ], for definition see S1 Appendix. These alternative depression categories were analysed with Bayesian systems-based lilly vércukornapló. Statistical methods We applied text-mining and conventional statistical methods to explore comorbid relations, see S1 Appendix.
For these computations we used in-house written R scripts together with the statistical programs included in the stats package of R [ 76 ]. To overcome the limitations of these conventional methods, we applied a Bayesian network Markov Chain Monte Carlo BN-MCMC method to explore the overall system of dependencies-independencies, visualized as an undirected graph with weighted edges [ 202123 — 2542 ].
We transformed odds ratios, risk ratios and χ2 p-values to the [0, 1] interval and we inverted the scale of χ2 p-values as follows. In this paper, we refer to as parametric association.