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  1. Article ; Online: Optimizing precision medicine for second-step depression treatment: a machine learning approach.

    Curtiss, Joshua / Smoller, Jordan W / Pedrelli, Paola

    Psychological medicine

    2024  , Page(s) 1–8

    Abstract: Background: Less than a third of patients with depression achieve successful remission with standard first-step antidepressant monotherapy. The process for determining appropriate second-step care is often based on clinical intuition and involves a ... ...

    Abstract Background: Less than a third of patients with depression achieve successful remission with standard first-step antidepressant monotherapy. The process for determining appropriate second-step care is often based on clinical intuition and involves a protracted course of trial and error, resulting in substantial patient burden and unnecessary delay in the provision of optimal treatment. To address this problem, we adopt an ensemble machine learning approach to improve prediction accuracy of remission in response to second-step treatments.
    Method: Data were derived from the Level 2 stage of the STAR*D dataset, which included 1439 patients who were randomized into one of seven different second-step treatment strategies after failing to achieve remission during first-step antidepressant treatment. Ensemble machine learning models, comprising several individual algorithms, were evaluated using nested cross-validation on 155 predictor variables including clinical and demographic measures.
    Results: The ensemble machine learning algorithms exhibited differential classification performance in predicting remission status across the seven second-step treatments. For the full set of predictors, AUC values ranged from 0.51 to 0.82 depending on the second-step treatment type. Predicting remission was most successful for cognitive therapy (AUC = 0.82) and least successful for other medication and combined treatment options (AUCs = 0.51-0.66).
    Conclusion: Ensemble machine learning has potential to predict second-step treatment. In this study, predictive performance varied by type of treatment, with greater accuracy in predicting remission in response to behavioral treatments than to pharmacotherapy interventions. Future directions include considering more informative predictor modalities to enhance prediction of second-step treatment response.
    Language English
    Publishing date 2024-03-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 217420-0
    ISSN 1469-8978 ; 0033-2917
    ISSN (online) 1469-8978
    ISSN 0033-2917
    DOI 10.1017/S0033291724000497
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Continuous-Time and Dynamic Suicide Attempt Risk Prediction with Neural Ordinary Differential Equations.

    Sheu, Yi-Han / Simm, Jaak / Wang, Bo / Lee, Hyunjoon / Smoller, Jordan W

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Suicide is one of the leading causes of death in the US, and the number of attributable deaths continues to increase. Risk of suicide-related behaviors (SRBs) is dynamic, and SRBs can occur across a continuum of time and locations. However, current SRB ... ...

    Abstract Suicide is one of the leading causes of death in the US, and the number of attributable deaths continues to increase. Risk of suicide-related behaviors (SRBs) is dynamic, and SRBs can occur across a continuum of time and locations. However, current SRB risk assessment methods, whether conducted by clinicians or through machine learning models, treat SRB risk as static and are confined to specific times and locations, such as following a hospital visit. Such a paradigm is unrealistic as SRB risk fluctuates and creates time gaps in the availability of risk scores. Here, we develop two closely related model classes, Event-GRU-ODE and Event-GRU-Discretized, that can predict the dynamic risk of events as a continuous trajectory based on Neural ODEs, an advanced AI model class for time series prediction. As such, these models can estimate changes in risk across the continuum of future time points, even without new observations, and can update these estimations as new data becomes available. We train and validate these models for SRB prediction using a large electronic health records database. Both models demonstrated high discrimination performance for SRB prediction (e.g., AUROC > 0.92 in the full, general cohort), serving as an initial step toward developing novel and comprehensive suicide prevention strategies based on dynamic changes in risk.
    Language English
    Publishing date 2024-02-27
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.25.24303343
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Multivariate genomic architecture of cortical thickness and surface area at multiple levels of analysis.

    Grotzinger, Andrew D / Mallard, Travis T / Liu, Zhaowen / Seidlitz, Jakob / Ge, Tian / Smoller, Jordan W

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 946

    Abstract: Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA). We model this multivariate system of genetic relationships by applying Genomic Structural Equation Modeling ...

    Abstract Recent work in imaging genetics suggests high levels of genetic overlap within cortical regions for cortical thickness (CT) and surface area (SA). We model this multivariate system of genetic relationships by applying Genomic Structural Equation Modeling (Genomic SEM) and parsimoniously define five genomic brain factors underlying both CT and SA along with a general factor capturing genetic overlap across all brain regions. We validate these factors by demonstrating the generalizability of the model to a semi-independent sample and show that the factors align with biologically and functionally relevant parcellations of the cortex. We apply Stratified Genomic SEM to identify specific categories of genes (e.g., neuronal cell types) that are disproportionately associated with pleiotropy across specific subclusters of brain regions, as indexed by the genomic factors. Finally, we examine genetic associations with psychiatric and cognitive correlates, finding that broad aspects of cognitive function are associated with a general factor for SA and that psychiatric associations are null. These analyses provide key insights into the multivariate genomic architecture of two critical features of the cerebral cortex.
    MeSH term(s) Genomics ; Cognition ; Brain ; Cerebral Cortex/diagnostic imaging ; Latent Class Analysis
    Language English
    Publishing date 2023-02-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-36605-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Integrating Electronic Health Records and Polygenic Risk to Identify Genetically Unrelated Comorbidities of Schizophrenia That May Be Modifiable.

    Vessels, Tess / Strayer, Nicholas / Lee, Hyunjoon / Choi, Karmel W / Zhang, Siwei / Han, Lide / Morley, Theodore J / Smoller, Jordan W / Xu, Yaomin / Ruderfer, Douglas M

    Biological psychiatry global open science

    2024  Volume 4, Issue 3, Page(s) 100297

    Abstract: Background: Patients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but ... ...

    Abstract Background: Patients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations.
    Methods: Phenome-wide comorbidity was calculated from electronic health records of 250,000 patients across 2 independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham); associations with schizophrenia polygenic risk scores were calculated across the same phenotypes in linked biobanks.
    Results: Schizophrenia comorbidity was significantly correlated across institutions (
    Conclusions: This work demonstrates the consistency and robustness of electronic health record-based schizophrenia comorbidities across independent institutions and with the existing literature. It identifies known and novel comorbidities with an absence of shared genetic risk, indicating other causes that may be modifiable and where further study of causal pathways could improve outcomes for patients.
    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Journal Article
    ISSN 2667-1743
    ISSN (online) 2667-1743
    DOI 10.1016/j.bpsgos.2024.100297
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The transition to parenthood, opportunity to drink, drinking, and alcohol use disorder.

    Axinn, William G / Banchoff, Emma / Cole, Faith / Ghimire, Dirgha J / Smoller, Jordan W

    Drug and alcohol dependence

    2022  Volume 241, Page(s) 109697

    Abstract: Background: This study used life histories from a setting of near universal marriage and childbearing (Nepal) to identify associations between both marital transitions and the transition into parenthood and alcohol use and disorder (AUD).: Methods: A ...

    Abstract Background: This study used life histories from a setting of near universal marriage and childbearing (Nepal) to identify associations between both marital transitions and the transition into parenthood and alcohol use and disorder (AUD).
    Methods: A retrospective, cross-sectional survey using life history calendars documented lifetime marital and childbearing histories of 4876 men and 5742 women aged 15-59 in 2016-18. The clinically validated, Nepal-specific Composite International Diagnostic Interview assessed first alcohol use opportunity, use, and disorder.
    Results: Being never married increased the odds of having the opportunity to drink for men (OR=1.30, 95% CI=1.14 - 1.48, p < 0.001) and women (OR=1.24, 95% CI=1.08 - 1.43, p = 0.003) compared to being married. While men were never married, widowed, or divorced they were at a greater risk of developing AUD. The transition to parenthood significantly increased the odds of AUD onset for men (OR=1.71, 95% CI=1.12 - 2.61, p = 0.013), independent of marital transitions. For women in this setting, becoming divorced increased the odds of having their first drink (OR=1.77, 95% CI=1.14 - 2.75, p = 0.011). Giving birth to a first child also increased the odds of first opportunity to drink for women (OR=1.30, 95% CI=1.07 - 1.57, p = 0.008).
    Conclusions: We found associations between marital transitions and AUD that are consistent with findings worldwide. In this setting of near universal childbearing, the transition into fatherhood increased the odds of postpartum AUD among men.
    MeSH term(s) Pregnancy ; Male ; Child ; Female ; Humans ; Alcoholism/epidemiology ; Alcoholism/diagnosis ; Marital Status ; Retrospective Studies ; Cross-Sectional Studies ; Divorce ; Alcohol Drinking/epidemiology
    Language English
    Publishing date 2022-11-11
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 519918-9
    ISSN 1879-0046 ; 0376-8716
    ISSN (online) 1879-0046
    ISSN 0376-8716
    DOI 10.1016/j.drugalcdep.2022.109697
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Impact of Stress on the Brain: Pathology, Treatment and Prevention.

    Ressler, Kerry J / Smoller, Jordan W

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2016  Volume 41, Issue 1, Page(s) 1–2

    MeSH term(s) Alzheimer Disease/etiology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Brain/metabolism ; Brain/pathology ; Humans ; Nerve Net/metabolism ; Nerve Net/pathology ; Stress, Psychological/complications ; Stress, Psychological/metabolism ; Stress, Psychological/pathology ; Treatment Outcome
    Language English
    Publishing date 2016-01
    Publishing country England
    Document type Editorial ; Introductory Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/npp.2015.306
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  7. Article ; Online: Polygenic risk for suicide attempt is associated with lifetime suicide attempt in US soldiers independent of parental risk.

    Stein, Murray B / Jain, Sonia / Papini, Santiago / Campbell-Sills, Laura / Choi, Karmel W / Martis, Brian / Sun, Xiaoying / He, Feng / Ware, Erin B / Naifeh, James A / Aliaga, Pablo A / Ge, Tian / Smoller, Jordan W / Gelernter, Joel / Kessler, Ronald C / Ursano, Robert J

    Journal of affective disorders

    2024  Volume 351, Page(s) 671–682

    Abstract: Background: Suicide is a leading cause of death worldwide. Whereas some studies have suggested that a direct measure of common genetic liability for suicide attempts (SA), captured by a polygenic risk score for SA (SA-PRS), explains risk independent of ... ...

    Abstract Background: Suicide is a leading cause of death worldwide. Whereas some studies have suggested that a direct measure of common genetic liability for suicide attempts (SA), captured by a polygenic risk score for SA (SA-PRS), explains risk independent of parental history, further confirmation would be useful. Even more unsettled is the extent to which SA-PRS is associated with lifetime non-suicidal self-injury (NSSI).
    Methods: We used summary statistics from the largest available GWAS study of SA to generate SA-PRS for two non-overlapping cohorts of soldiers of European ancestry. These were tested in multivariable models that included parental major depressive disorder (MDD) and parental SA.
    Results: In the first cohort, 417 (6.3 %) of 6573 soldiers reported lifetime SA and 1195 (18.2 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.26, 95%CI:1.13-1.39, p < 0.001] per standardized unit SA-PRS]. In the second cohort, 204 (4.2 %) of 4900 soldiers reported lifetime SA, and 299 (6.1 %) reported lifetime NSSI. In a multivariable model that included parental history of MDD and parental history of SA, SA-PRS remained significantly associated with lifetime SA [aOR = 1.20, 95%CI:1.04-1.38, p = 0.014]. A combined analysis of both cohorts yielded similar results. In neither cohort or in the combined analysis was SA-PRS significantly associated with NSSI.
    Conclusions: PRS for SA conveys information about likelihood of lifetime SA (but not NSSI, demonstrating specificity), independent of self-reported parental history of MDD and parental history of SA.
    Limitations: At present, the magnitude of effects is small and would not be immediately useful for clinical decision-making or risk-stratified prevention initiatives, but this may be expected to improve with further iterations. Also critical will be the extension of these findings to more diverse populations.
    MeSH term(s) Humans ; Suicide, Attempted ; Suicidal Ideation ; Depressive Disorder, Major/epidemiology ; Depressive Disorder, Major/genetics ; Military Personnel ; Risk Factors ; Self-Injurious Behavior/epidemiology ; Self-Injurious Behavior/genetics ; Parents
    Language English
    Publishing date 2024-02-01
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 135449-8
    ISSN 1573-2517 ; 0165-0327
    ISSN (online) 1573-2517
    ISSN 0165-0327
    DOI 10.1016/j.jad.2024.01.254
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  8. Article ; Online: Integrative analysis of genomic and exposomic influences on youth mental health.

    Choi, Karmel W / Wilson, Marina / Ge, Tian / Kandola, Aaron / Patel, Chirag J / Lee, S Hong / Smoller, Jordan W

    Journal of child psychology and psychiatry, and allied disciplines

    2022  Volume 63, Issue 10, Page(s) 1196–1205

    Abstract: Background: Understanding complex influences on mental health problems in young people is needed to inform early prevention strategies. Both genetic and environmental factors are known to influence youth mental health, but a more comprehensive picture ... ...

    Abstract Background: Understanding complex influences on mental health problems in young people is needed to inform early prevention strategies. Both genetic and environmental factors are known to influence youth mental health, but a more comprehensive picture of their interplay, including wide-ranging environmental exposures - that is, the exposome - is needed. We perform an integrative analysis of genomic and exposomic data in relation to internalizing and externalizing symptoms in a cohort of 4,314 unrelated youth from the Adolescent Brain and Cognitive Development (ABCD) Study.
    Methods: Using novel GREML-based approaches, we model the variance in internalizing and externalizing symptoms explained by additive and interactive influences from the genome (G) and modeled exposome (E) consisting of up to 133 variables at the family, peer, school, neighborhood, life event, and broader environmental levels, including genome-by-exposome (G × E) and exposome-by-exposome (E × E) effects.
    Results: A best-fitting integrative model with G, E, and G × E components explained 35% and 63% of variance in youth internalizing and externalizing symptoms, respectively. Youth in the top quintile of model-predicted risk accounted for the majority of individuals with clinically elevated symptoms at follow-up (60% for internalizing; 72% for externalizing). Of note, different domains of environmental exposures were most impactful for internalizing (life events) and externalizing (contextual including family, school, and peer-level factors) symptoms. In addition, variance explained by G × E contributions was substantially larger for externalizing (33%) than internalizing (13%) symptoms.
    Conclusions: Advanced statistical genetic methods in a longitudinal cohort of youth can be leveraged to address fundamental questions about the role of 'nature and nurture' in developmental psychopathology.
    MeSH term(s) Adolescent ; Genomics ; Humans ; Mental Health ; Psychopathology ; Schools
    Language English
    Publishing date 2022-08-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 218136-8
    ISSN 1469-7610 ; 0021-9630 ; 0373-8086
    ISSN (online) 1469-7610
    ISSN 0021-9630 ; 0373-8086
    DOI 10.1111/jcpp.13664
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  9. Article ; Online: How do experts in psychiatric genetics view the clinical utility of polygenic risk scores for schizophrenia?

    Moorthy, Tiahna / Nguyen, Huyen / Chen, Ying / Austin, Jehannine / Smoller, Jordan W / Hercher, Laura / Sabatello, Maya

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

    2023  Volume 192, Issue 7-8, Page(s) 161–170

    Abstract: Polygenic risk scores (PRS) are promising for identifying common variant-related inheritance for psychiatric conditions but their integration into clinical practice depends on their clinical utility and psychiatrists' understanding of PRS. Our online ... ...

    Abstract Polygenic risk scores (PRS) are promising for identifying common variant-related inheritance for psychiatric conditions but their integration into clinical practice depends on their clinical utility and psychiatrists' understanding of PRS. Our online survey explored these issues with 276 professionals working in psychiatric genetics (RR: 19%). Overall, participants demonstrated knowledge of how to interpret PRS results. Their performance on knowledge-based questions was positively correlated with participants' self-reported familiarity with PRS (r = 0.21, p = 0.0006) although differences were not statistically significant (Wald Chi-square = 3.29, df = 1, p = 0.07). However, only 48.9% of all participants answered all knowledge questions correctly. Many participants (56.5%), especially researchers (42%), indicated having at least occasional conversations about the role of genetics in psychiatric conditions with patients and/or family members. Most participants (62.7%) indicated that PRS are not yet sufficiently robust for assessment of susceptibility to schizophrenia; most significant obstacles were low predictive power and lack of population diversity in available PRS (selected, respectively, by 53.6% and 29.3% of participants). Nevertheless, 89.8% of participants were optimistic about the use of PRS in the next 10 years, suggesting a belief that current shortcomings could be addressed. Our findings inform about the perceptions of psychiatric professionals regarding PRS and the application of PRS in psychiatry.
    MeSH term(s) Humans ; Schizophrenia/genetics ; Risk Factors ; Multifactorial Inheritance/genetics ; Heredity ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease
    Language English
    Publishing date 2023-05-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2108616-3
    ISSN 1552-485X ; 1552-4841 ; 0148-7299
    ISSN (online) 1552-485X
    ISSN 1552-4841 ; 0148-7299
    DOI 10.1002/ajmg.b.32939
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  10. Article: Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models.

    Morley, Theodore J / Willimitis, Drew / Ripperger, Michael / Lee, Hyunjoon / Han, Lide / Zhou, Yu / Kang, Jooeun / Davis, Lea K / Smoller, Jordan W / Choi, Karmel W / Walsh, Colin G / Ruderfer, Douglas M

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results across studies. Here, we performed ... ...

    Abstract The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results across studies. Here, we performed multiple modeling experiments integrating clinical and demographic data from electronic health records (EHR) and genetic data to understand which decision points may affect performance. Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from two large independent health systems and polygenic risk scores (PRS) were generated across all patients with genetic data in the corresponding biobanks. Crohn's disease was used as the model phenotype based on its substantial genetic component, established EHR-based definition, and sufficient prevalence for model training and testing. We investigated the impact of PRS integration method, as well as choices regarding training sample, model complexity, and performance metrics. Overall, our results show that including PRS resulted in higher performance by some metrics but the gain in performance was only robust when combined with demographic data alone. Improvements were inconsistent or negligible after including additional clinical information. The impact of genetic information on performance also varied by PRS integration method, with a small improvement in some cases from combining PRS with the output of a clinical model (late-fusion) compared to its inclusion an additional feature (early-fusion). The effects of other modeling decisions varied between institutions though performance increased with more compute-intensive models such as random forest. This work highlights the importance of considering methodological decision points in interpreting the impact on prediction performance when including PRS information in clinical models.
    Language English
    Publishing date 2023-11-01
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.01.23297927
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