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1.  Major depressive disorder subtypes to predict long-term course 
Depression and anxiety  2014;31(9):765-777.
Background
Variation in course of major depressive disorder (MDD) is not strongly predicted by existing subtype distinctions. A new subtyping approach is considered here.
Methods
Two data mining techniques, ensemble recursive partitioning and Lasso generalized linear models (GLMs) followed by k-means cluster analysis, are used to search for subtypes based on index episode symptoms predicting subsequent MDD course in the World Mental Health (WMH) Surveys. The WMH surveys are community surveys in 16 countries. Lifetime DSM-IV MDD was reported by 8,261 respondents. Retrospectively reported outcomes included measures of persistence (number of years with an episode; number of with an episode lasting most of the year) and severity (hospitalization for MDD; disability due to MDD).
Results
Recursive partitioning found significant clusters defined by the conjunctions of early onset, suicidality, and anxiety (irritability, panic, nervousness-worry-anxiety) during the index episode. GLMs found additional associations involving a number of individual symptoms. Predicted values of the four outcomes were strongly correlated. Cluster analysis of these predicted values found three clusters having consistently high, intermediate, or low predicted scores across all outcomes. The high-risk cluster (30.0% of respondents) accounted for 52.9-69.7% of high persistence and severity and was most strongly predicted by index episode severe dysphoria, suicidality, anxiety, and early onset. A total symptom count, in comparison, was not a significant predictor.
Conclusions
Despite being based on retrospective reports, results suggest that useful MDD subtyping distinctions can be made using data mining methods. Further studies are needed to test and expand these results with prospective data.
doi:10.1002/da.22233
PMCID: PMC5125445  PMID: 24425049
Epidemiology; Depression; Anxiety/Anxiety Disorders; Suicide/Self Harm; Panic Attacks
2.  Multiple risk factors predict recurrence of major depressive disorder in women 
Background
It is difficult to predict recurrence of depressive episodes in patients with major depression (MD): evidence for many risk factors is inconsistent and general prediction algorithms are lacking. The aim of this study was to develop a prediction model for recurrence of depressive episodes in women using improved methodology.
Methods
We used prospective data from a general population sample of female twins with a last-year MD episode (n=194). A rich set of baseline predictors was analyzed with Cox proportional hazards regression subject to elastic net regularization to find a model predicting recurrence of depressive episodes. Prediction accuracy of the model was assessed in an independent test sample (n=133), which was limited by the unavailability of a number of key predictors.
Results
A wide variety of risk factors predicted recurrence of depressive episodes in women: depressive and anxiety symptoms during the index episode, the level of symptoms at the moment of interview, psychiatric and family history, early and recent adverse life events, being unmarried, and problems with friends and finances. Kaplan Meier estimated survival curves showed that the model differentiated between patients at higher and lower risk for recurrence; estimated areas under the curve were in the range of 0.61-0.79.
Limitations
Despite our rich set of predictors, certain potentially relevant variables were not available, such as biological measures, chronic somatic diseases, and treatment status.
Conclusions
Recurrence of episodes of MD in women is highly multifactorial. Future studies should take this into account for the development of clinically useful prediction algorithms.
doi:10.1016/j.jad.2015.03.045
PMCID: PMC4504430  PMID: 25881281
Major depressive disorder; Prediction; Recurrence; Women
3.  Testing a machine-learning algorithm to predict the persistence and severity of major depressive disorder from baseline self-reports 
Molecular psychiatry  2016;21(10):1366-1371.
Heterogeneity of major depressive disorder (MDD) illness course complicates clinical decision-making. While efforts to use symptom profiles or biomarkers to develop clinically useful prognostic subtypes have had limited success, a recent report showed that machine learning (ML) models developed from self-reports about incident episode characteristics and comorbidities among respondents with lifetime MDD in the World Health Organization World Mental Health (WMH) Surveys predicted MDD persistence, chronicity, and severity with good accuracy. We report results of model validation in an independent prospective national household sample of 1,056 respondents with lifetime MDD at baseline. The WMH ML models were applied to these baseline data to generate predicted outcome scores that were compared to observed scores assessed 10–12 years after baseline. ML model prediction accuracy was also compared to that of conventional logistic regression models. Area under the receiver operating characteristic curve (AUC) based on ML (.63 for high chronicity and .71–.76 for the other prospective outcomes) was consistently higher than for the logistic models (.62–.70) despite the latter models including more predictors. 34.6–38.1% of respondents with subsequent high persistence-chronicity and 40.8–55.8% with the severity indicators were in the top 20% of the baseline ML predicted risk distribution, while only 0.9% of respondents with subsequent hospitalizations and 1.5% with suicide attempts were in the lowest 20% of the ML predicted risk distribution. These results confirm that clinically useful MDD risk stratification models can be generated from baseline patient self-reports and that ML methods improve on conventional methods in developing such models.
doi:10.1038/mp.2015.198
PMCID: PMC4935654  PMID: 26728563
4.  Psychiatric comorbidity: fact or artifact? 
The frequent occurrence of comorbidity has brought about an extensive theoretical debate in psychiatry. Why are the rates of psychiatric comorbidity so high and what are their implications for the ontological and epistemological status of comorbid psychiatric diseases? Current explanations focus either on classification choices or on causal ties between disorders. Based on empirical and philosophical arguments, we propose a conventionalist interpretation of psychiatric comorbidity instead. We argue that a conventionalist approach fits well with research and clinical practice and resolves two problems for psychiatric diseases: experimenter’s regress and arbitrariness.
doi:10.1007/s11017-015-9321-0
PMCID: PMC4320768  PMID: 25636962
Comorbidity; Psychiatric disorders; DSM; Disease classification; Conventionalism
5.  Sex dependent risk factors for mortality after myocardial infarction: individual patient data meta-analysis 
BMC Medicine  2014;12:242.
Background
Although a number of risk factors are known to predict mortality within the first years after myocardial infarction, little is known about interactions between risk factors, whereas these could contribute to accurate differentiation of patients with higher and lower risk for mortality. This study explored the effect of interactions of risk factors on all-cause mortality in patients with myocardial infarction based on individual patient data meta-analysis.
Methods
Prospective data for 10,512 patients hospitalized for myocardial infarction were derived from 16 observational studies (MINDMAPS). Baseline measures included a broad set of risk factors for mortality such as age, sex, heart failure, diabetes, depression, and smoking. All two-way and three-way interactions of these risk factors were included in Lasso regression analyses to predict time-to-event related all-cause mortality. The effect of selected interactions was investigated with multilevel Cox regression models.
Results
Lasso regression selected five two-way interactions, of which four included sex. The addition of these interactions to multilevel Cox models suggested differential risk patterns for males and females. Younger women (age <50) had a higher risk for all-cause mortality than men in the same age group (HR 0.7 vs. 0.4), while men had a higher risk than women if they had depression (HR 1.4 vs. 1.1) or a low left ventricular ejection fraction (HR 1.7 vs. 1.3). Predictive accuracy of the Cox model was better for men than for women (area under the curves: 0.770 vs. 0.754).
Conclusions
Interactions of well-known risk factors for all-cause mortality after myocardial infarction suggested important sex differences. This study gives rise to a further exploration of prediction models to improve risk assessment for men and women after myocardial infarction.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0242-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0242-y
PMCID: PMC4292997  PMID: 25515680
All-cause mortality; Interactions; Myocardial infarction; Prediction; Risk factors; Sex
6.  Data-driven subtypes of major depressive disorder: a systematic review 
BMC Medicine  2012;10:156.
Background
According to current classification systems, patients with major depressive disorder (MDD) may have very different combinations of symptoms. This symptomatic diversity hinders the progress of research into the causal mechanisms and treatment allocation. Theoretically founded subtypes of depression such as atypical, psychotic, and melancholic depression have limited clinical applicability. Data-driven analyses of symptom dimensions or subtypes of depression are scarce. In this systematic review, we examine the evidence for the existence of data-driven symptomatic subtypes of depression.
Methods
We undertook a systematic literature search of MEDLINE, PsycINFO and Embase in May 2012. We included studies analyzing the depression criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) of adults with MDD in latent variable analyses.
Results
In total, 1176 articles were retrieved, of which 20 satisfied the inclusion criteria. These reports described a total of 34 latent variable analyses: 6 confirmatory factor analyses, 6 exploratory factor analyses, 12 principal component analyses, and 10 latent class analyses. The latent class techniques distinguished 2 to 5 classes, which mainly reflected subgroups with different overall severity: 62 of 71 significant differences on symptom level were congruent with a latent class solution reflecting severity. The latent class techniques did not consistently identify specific symptom clusters. Latent factor techniques mostly found a factor explaining the variance in the symptoms depressed mood and interest loss (11 of 13 analyses), often complemented by psychomotor retardation or fatigue (8 of 11 analyses). However, differences in found factors and classes were substantial.
Conclusions
The studies performed to date do not provide conclusive evidence for the existence of depressive symptom dimensions or symptomatic subtypes. The wide diversity of identified factors and classes might result either from the absence of patterns to be found, or from the theoretical and modeling choices preceding analysis.
doi:10.1186/1741-7015-10-156
PMCID: PMC3566979  PMID: 23210727
Major depressive disorder; subtypes; depressive symptoms; latent factor analyses; latent class analyses

Results 1-6 (6)