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1.  Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women 
PLoS ONE  2014;9(1):e86674.
Background
The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years.
Principal findings
We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders.
Conclusions
In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype.
doi:10.1371/journal.pone.0086674
PMCID: PMC3909008  PMID: 24497966
2.  Childhood Sexual Abuse and the Development of Recurrent Major Depression in Chinese Women 
PLoS ONE  2014;9(1):e87569.
Background
Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set?
Method
Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression.
Results
We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19–5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58–3.15), genital (OR 5.24, 95% CI 3.52–8.15) and intercourse (OR 10.65, 95% CI 5.56–23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11–2.27) and phobia (OR 1.41, 95%CI 1.09–1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20–1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02–2.02). Intercourse (OR 3.47, 95%CI 1.66–8.22), use of force and threats (OR 1.95, 95%CI 1.05–3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20–1.64) were significantly associated with recurrent MD.
Conclusions
In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD.
doi:10.1371/journal.pone.0087569
PMCID: PMC3906190  PMID: 24489940
3.  Clinical Features of Patients with Dysthymia in a Large Cohort of Han Chinese Women with Recurrent Major Depression 
PLoS ONE  2013;8(12):e83490.
Background
Dysthymia is a form of chronic mild depression that has a complex relationship with major depressive disorder (MDD). Here we investigate the role of environmental risk factors, including stressful life events and parenting style, in patients with both MDD and dysthymia. We ask whether these risk factors act in the same way in MDD with and without dysthymia.
Results
We examined the clinical features in 5,950 Han Chinese women with MDD between 30–60 years of age across China. We confirmed earlier results by replicating prior analyses in 3,950 new MDD cases. There were no significant differences between the two data sets. We identified sixteen stressful life events that significantly increase the risk of dysthymia, given the presence of MDD. Low parental warmth, from either mother or father, increases the risk of dysthymia. Highly threatening but short-lived threats (such as rape) are more specific for MDD than dysthymia. While for MDD more severe life events show the largest odds ratio versus controls, this was not seen for cases of MDD with or without dysthymia.
Conclusions
There are increased rates of stressful life events in MDD with dysthymia, but the impact of life events on susceptibility to dysthymia with MDD differs from that seen for MDD alone. The pattern does not fit a simple dose-response relationship, suggesting that there are moderating factors involved in the relationship between environmental precipitants and the onset of dysthymia. It is possible that severe life events in childhood events index a general susceptibility to chronic depression, rather than acting specifically as risk factors for dysthymia.
doi:10.1371/journal.pone.0083490
PMCID: PMC3873934  PMID: 24386213
4.  Suicidal Risk Factors of Recurrent Major Depression in Han Chinese Women 
PLoS ONE  2013;8(11):e80030.
The relationship between suicidality and major depression is complex. Socio- demography, clinical features, comorbidity, clinical symptoms, and stressful life events are important factors influencing suicide in major depression, but these are not well defined. Thus, the aim of the present study was to assess the associations between the above-mentioned factors and suicide ideation, suicide plan, and suicide attempt in 6008 Han Chinese women with recurrent major depression (MD). Patients with any suicidality had significantly more MD symptoms, a significantly greater number of stressful life events, a positive family history of MD, a greater number of episodes, a significant experience of melancholia, and earlier age of onset. Comorbidity with dysthymia, generalized anxiety disorder (GAD), social phobia, and animal phobia was seen in suicidal patients. The present findings indicate that specific factors act to increase the likelihood of suicide in MD. Our results may help improve the clinical assessment of suicide risk in depressed patients, especially for women.
doi:10.1371/journal.pone.0080030
PMCID: PMC3842272  PMID: 24312196
5.  A Fast Exact k-Nearest Neighbors Algorithm for High Dimensional Search Using k-Means Clustering and Triangle Inequality 
The k-nearest neighbors (k-NN) algorithm is a widely used machine learning method that finds nearest neighbors of a test object in a feature space. We present a new exact k-NN algorithm called kMkNN (k-Means for k-Nearest Neighbors) that uses the k-means clustering and the triangle inequality to accelerate the searching for nearest neighbors in a high dimensional space. The kMkNN algorithm has two stages. In the buildup stage, instead of using complex tree structures such as metric trees, kd-trees, or ball-tree, kMkNN uses a simple k-means clustering method to preprocess the training dataset. In the searching stage, given a query object, kMkNN finds nearest training objects starting from the nearest cluster to the query object and uses the triangle inequality to reduce the distance calculations. Experiments show that the performance of kMkNN is surprisingly good compared to the traditional k-NN algorithm and tree-based k-NN algorithms such as kd-trees and ball-trees. On a collection of 20 datasets with up to 106 records and 104 dimensions, kMkNN shows a 2-to 80-fold reduction of distance calculations and a 2- to 60-fold speedup over the traditional k-NN algorithm for 16 datasets. Furthermore, kMkNN performs significant better than a kd-tree based k-NN algorithm for all datasets and performs better than a ball-tree based k-NN algorithm for most datasets. The results show that kMkNN is effective for searching nearest neighbors in high dimensional spaces.
doi:10.1016/j.patcog.2010.01.003
PMCID: PMC3255306  PMID: 22247818
6.  Resemblance of Symptoms for Major Depression Assessed at Interview versus from Hospital Record Review 
PLoS ONE  2012;7(1):e28734.
Background
Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies.
Principal findings
We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors were identified for twelve symptoms from medical records and the same four factors emerged from analysis of structured interviews. Factor congruencies were high but the correlation of factors between interviews and records were modest (i.e. +0.2 to +0.4).
Conclusions
Structured interviews and medical records are highly concordant for age of onset, and the number and length of episodes, but agree more modestly for individual symptoms and symptom factors. The modesty of these correlations probably arises from multiple factors including i) inconsistency in the definition of the worst episode, ii) inaccuracies in self-report and iii) difficulties in coding medical records where symptoms were recorded solely for clinical purposes.
doi:10.1371/journal.pone.0028734
PMCID: PMC3256142  PMID: 22247760
7.  Oxidative Stress Mediated-Alterations of the MicroRNA Expression Profile in Mouse Hippocampal Neurons 
Oxidative stress plays a critical role in the etiology and pathogenesis of neurodegenerative disorders, and the molecular mechanisms that control the neuron response to ROS have been extensively studied. However, the oxidative stress-effect on miRNA expression in hippocampal neurons has not been investigated, and little is known on the effect of ROS-modulated miRNAs on cell function. In this study, H2O2 was used to stimulate the mouse primary hippocampal neurons to develop an oxidative stress cell model. The alterations of miRNAs expression were detected by microarray analysis and five miRNAs were validated by real-time RT-PCR. The bioinformatic analysis of deregulated miRNAs was performed to determine their potential roles in the pathogenesis of neurological disorders. We found that H2O2 mediated a total of 101 deregulated miRNAs, which mainly took part in the regulation of the MAPK pathway. Among them, miR-135b and miR-708 were up-regulated significantly and their targets were predicted to be involved in DNA recombination, protein ubiquitination, protein autophosphorylation and development of neurons. These results demonstrated that oxidative stress alters the miRNA expression profile of hippocampal neurons, and the deregulated miRNAs might play a potential role in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD).
doi:10.3390/ijms131216945
PMCID: PMC3546732  PMID: 23443129
oxidative stress; microRNA; hippocampal neurons; array analysis; Alzheimer disease
8.  A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia☆ 
Journal of Affective Disorders  2011;135(1-3):106-110.
Background
The relationship between major depressive disorder (MDD) and dysthymia, a form of chronic depression, is complex. The two conditions are highly comorbid and it is unclear whether they are two separate disease entities. We investigated the extent to which patients with dysthymia superimposed on major depression can be distinguished from those with recurrent MDD.
Methods
We examined the clinical features in 1970 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and dysthymia and between dysthymia and disorders comorbid with major depression.
Results
The 354 cases with dysthymia had more severe MDD than those without, with more episodes of MDD and greater co-morbidity for anxiety disorders. Patients with dysthymia had higher neuroticism scores and were more likely to have a family history of MDD. They were also more likely to have suffered serious life events.
Limitations
Results were obtained in a clinically ascertained sample of Chinese women and may not generalize to community-acquired samples or to other populations. It is not possible to determine whether the associations represent causal relationships.
Conclusions
The additional diagnosis of dysthymia in Chinese women with recurrent MDD defines a meaningful and potentially important subtype. We conclude that in some circumstances it is possible to distinguish double depression from recurrent MDD.
doi:10.1016/j.jad.2011.06.051
PMCID: PMC3221043  PMID: 21824660
Major depressive disorder; Dysthymia; Symptom; Comorbidity
9.  Age at onset of major depressive disorder in Han Chinese women: Relationship with clinical features and family history☆ 
Journal of Affective Disorders  2011;135(1-3):89-94.
Background
Individuals with early-onset depression may be a clinically distinct group with particular symptom patterns, illness course, comorbidity and family history. This question has not been previously investigated in a Han Chinese population.
Methods
We examined the clinical features of 1970 Han Chinese women with DSM-IV major depressive disorder (MDD) between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models was used to determine the association between age at onset (AAO) with continuous, binary and discrete characteristic clinical features of MDD.
Results
Earlier AAO was associated with more suicidal ideation and attempts and higher neuroticism, but fewer sleep, appetite and weight changes. Patients with an earlier AAO were more likely to suffer a chronic course (longer illness duration, more MDD episodes and longer index episode), increased rates of MDD in their parents and a lower likelihood of marriage. They tend to have higher comorbidity with anxiety disorders (general anxiety disorder, social phobia and agoraphobia) and dysthymia.
Conclusions
Early AAO in MDD may be an index of a more severe, highly comorbid and familial disorder. Our findings indicate that the features of MDD in China are similar to those reported elsewhere in the world.
doi:10.1016/j.jad.2011.06.056
PMCID: PMC3210897  PMID: 21782247
Major depressive disorder; Age at onset; Symptom; Comorbidity
10.  The Upper and Lower Bounds of the Prediction Accuracies of Ensemble Methods for Binary Classification 
Ensemble methods have been widely used to improve prediction accuracy over individual classifiers. In this paper, we achieve a few results about the prediction accuracies of ensemble methods for binary classification that are missed or misinterpreted in previous literature. First we show the upper and lower bounds of the prediction accuracies (i.e. the best and worst possible prediction accuracies) of ensemble methods. Next we show that an ensemble method can achieve > 0.5 prediction accuracy, while individual classifiers have < 0.5 prediction accuracies. Furthermore, for individual classifiers with different prediction accuracies, the average of the individual accuracies determines the upper and lower bounds. We perform two experiments to verify the results and show that it is hard to achieve the upper and lower bounds accuracies by random individual classifiers and better algorithms need to be developed.
doi:10.1109/ICMLA.2010.62
PMCID: PMC3156487  PMID: 21853162
ensemble methods; binary classification; prediction accuracy; upper bound; lower bound
11.  Non-Alignment Features Based Enzyme/Non-Enzyme Classification Using an Ensemble Method 
As a growing number of protein structures are resolved without known functions, using computational methods to help predict protein functions from the structures becomes more and more important. Some computational methods predict protein functions by aligning to homologous proteins with known functions, but they fail to work if such homology cannot be identified. In this paper we classify enzymes/non-enzymes using non-alignment features. We propose a new ensemble method that includes three support vector machines (SVM) and two k-nearest neighbor algorithms (k-NN) and uses a simple majority voting rule. The test on a data set of 697 enzymes and 480 non-enzymes adapted from Dobson and Doig shows 85.59% accuracy in a 10-fold cross validation and 86.49% accuracy in a leave-one-out validation. The prediction accuracy is much better than other non-alignment features based methods and even slightly better than alignment features based methods. To our knowledge, our method is the first time to use ensemble methods to classify enzymes/non-enzymes and is superior over a single classifier.
doi:10.1109/ICMLA.2010.167
PMCID: PMC3091888  PMID: 21572553
enzyme/non-enzyme classification; ensemble methods; support vector machine; k-nearest neighbour algorithm
12.  RNABC: Forward Kinematics to Reduce All-Atom Steric Clashes in RNA Backbone 
Journal of mathematical biology  2007;56(1-2):253-278.
Although accurate details in RNA structure are of great importance for understanding RNA function, the backbone conformation is difficult to determine, and most existing RNA structures show serious steric clashes (≥ 0.4Å overlap) when hydrogen atoms are taken into account. We have developed a program called RNABC (RNA Backbone Correction) that performs local perturbations to search for alternative conformations that avoid those steric clashes or other local geometry problems. Its input is an all-atom coordinate file for an RNA crystal structure (usually from the MolProbity web service), with problem areas specified. RNABC rebuilds a suite (the unit from sugar to sugar) by anchoring the phosphorus and base positions, which are clearest in crystallographic electron density, and reconstructing the other atoms using forward kinematics. Geometric parameters are constrained within user-specified tolerance of canonical or original values, and torsion angles are constrained to ranges defined through empirical database analyses. Several optimizations reduce the time required to search the many possible conformations. The output results are clustered and presented to the user, who can choose whether to accept one of the alternative conformations.
Two test evaluations show the effectiveness of RNABC, first on the S-motifs from 42 RNA structures, and second on the worst problem suites (clusters of bad clashes, or serious sugar pucker outliers) in 25 unrelated RNA structures. Among the 101 S-motifs, 88 had diagnosed problems, and RNABC produced clash-free conformations with acceptable geometry for 71 of those (about 80%). For the 154 worst problem suites, RNABC proposed alternative conformations for 72. All but 8 of those were judged acceptable after examining electron density (where available) and local conformation. Thus, even for these worst cases, nearly half the time RNABC suggested corrections suitable to initiate further crystallographic refinement. The program is available from http://kinemage.biochem.duke.edu.
doi:10.1007/s00285-007-0082-x
PMCID: PMC2153530  PMID: 17401565
kinematic chain; RNA backbone conformation; RNA backbone adjustment; RNA crystallography; automated rebuilding; steric clash; S-motifs; all-atom contacts; structure validation
13.  MolProbity: all-atom contacts and structure validation for proteins and nucleic acids 
Nucleic Acids Research  2007;35(Web Server issue):W375-W383.
MolProbity is a general-purpose web server offering quality validation for 3D structures of proteins, nucleic acids and complexes. It provides detailed all-atom contact analysis of any steric problems within the molecules as well as updated dihedral-angle diagnostics, and it can calculate and display the H-bond and van der Waals contacts in the interfaces between components. An integral step in the process is the addition and full optimization of all hydrogen atoms, both polar and nonpolar. New analysis functions have been added for RNA, for interfaces, and for NMR ensembles. Additionally, both the web site and major component programs have been rewritten to improve speed, convenience, clarity and integration with other resources. MolProbity results are reported in multiple forms: as overall numeric scores, as lists or charts of local problems, as downloadable PDB and graphics files, and most notably as informative, manipulable 3D kinemage graphics shown online in the KiNG viewer. This service is available free to all users at http://molprobity.biochem.duke.edu.
doi:10.1093/nar/gkm216
PMCID: PMC1933162  PMID: 17452350
14.  Patterns of co-morbidity with anxiety disorders in Chinese women with recurrent major depression 
Psychological Medicine  2011;42(6):1239-1248.
Background
Studies conducted in Europe and the USA have shown that co-morbidity between major depressive disorder (MDD) and anxiety disorders is associated with various MDD-related features, including clinical symptoms, degree of familial aggregation and socio-economic status. However, few studies have investigated whether these patterns of association vary across different co-morbid anxiety disorders. Here, using a large cohort of Chinese women with recurrent MDD, we examine the prevalence and associated clinical features of co-morbid anxiety disorders.
Method
A total of 1970 female Chinese MDD patients with or without seven co-morbid anxiety disorders [including generalized anxiety disorder (GAD), panic disorder, and five phobia subtypes] were ascertained in the CONVERGE study. Generalized linear models were used to model association between co-morbid anxiety disorders and various MDD features.
Results
The lifetime prevalence rate for any type of co-morbid anxiety disorder is 60.2%. Panic and social phobia significantly predict an increased family history of MDD. GAD and animal phobia predict an earlier onset of MDD and a higher number of MDD episodes, respectively. Panic and GAD predict a higher number of DSM-IV diagnostic criteria. GAD and blood-injury phobia are both significantly associated with suicidal attempt with opposite effects. All seven co-morbid anxiety disorders predict higher neuroticism.
Conclusions
Patterns of co-morbidity between MDD and anxiety are consistent with findings from the US and European studies; the seven co-morbid anxiety disorders are heterogeneous when tested for association with various MDD features.
doi:10.1017/S003329171100273X
PMCID: PMC3339636  PMID: 22126712
Co-morbid anxiety disorders; major depression
15.  CLINICAL PREDICTORS OF FAMILIAL DEPRESSION IN HAN CHINESE WOMEN 
Depression and Anxiety  2011;29(1):10-15.
Background
A number of clinical features potentially reflect an individual's familial vulnerability to major depression (MD), including early age at onset, recurrence, impairment, episode duration, and the number and pattern of depressive symptoms. However, these results are drawn from studies that have exclusively examined individuals from a European ethnic background. We investigated which clinical features of depressive illness index familial vulnerability in Han Chinese females with MD.
Methods
We used lifetime MD and associated clinical features assessed at personal interview in 1,970 Han Chinese women with DSM-IV MD between 30–60 years of age. Odds Ratios were calculated by logistic regression.
Results
Individuals with a high familial risk for MD are characterized by severe episodes of MD without known precipitants (such as stress life events) and are less likely to feel irritable/angry or anxious/nervous.
Conclusions
The association between family history of MD and the lack of a precipitating stressor, traditionally a characteristic of endogenous or biological depression, may reflect the association seen in other samples between recurrent MD and a positive family history. The symptomatic associations we have seen may reflect a familial predisposition to other dimensions of psychopathology, such as externalizing disorders or anxiety states. Depression and Anxiety 0:1–6, 2011. © 2011 Wiley-Liss, Inc.
doi:10.1002/da.20878
PMCID: PMC3429856  PMID: 22065525
major depression; family history; symptom; life events

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