Predicting suicidality using a combined genomic and clinical risk assessment

Abstract

Biomarkers and methods for screening expression levels of the biomarkers for predicting suicidality (referred herein to suicidal ideation and actions, future hospitalizations and suicide completion) are disclosed. Also disclosed are quantitative questionnaires and mobile applications for assessing affective state and for assessing socio-demographic and psychological suicide risk factors, and their use to compute scores that can predict suicidality. Finally, an algorithm that combines biomarkers and computer apps for identifying subjects who are at risk for committing suicide is disclosed, as well as methods to mitigate and prevent suicidality based on the biomarkers and computer apps.

1 - 20 . (canceled) 
     
     
         21 . A method for assessing and mitigating suicidality in a subject in need thereof, comprising:
 determining an expression level of a panel of biomarkers in a biological sample from the subject, computing a score for the panel, based on the gene expression data for the biomarkers in the panel, which is z-scored for each of the biomarkers in the biomarker panel with a reference database, multiplying each biomarker z-scored value by a weight coefficient related to their functional evidence of involvement in suicidality to obtain a second score for each biomarker of the biomarker panel, with the resulting values for the increased in expression (risk) biomarkers being added, and the resulting values for the decreased in expression (protective) biomarkers being subtracted,   wherein when the subject is male;   the panel of biomarkers comprises:   (i) solute carrier family 4 (sodium bicarbonate cotransporter), member 4 (SLC4A4), cell adhesion molecule 1 CADM1, dystrobrevin, alpha (DTNA), spermidine/spermine Nl-acetyl transferase 1 (SAT1), interleukin 6 (IL-6), RAS-like family 11 member B (RASL11B), glutamate receptor, Ionotropic, kainate 2 (GRIK2), histone cluster 1, H2bo (HIST1H2BO), jun proto—oncogene (JUN), and GRB2-associated binding protein 1 (GAB1), wherein the expression level of the biomarker(s) in the sample is increased relative to a reference expression level, denoting increased suicidality; or   (ii) spindle and kinetochore associated complex subunit 2 (SKA2), CAP-GLY domain containing linker protein family, member 4 (CLIP4), kinesin family member 2C (KIF2C), kelch domain containing 3 (KLHDC3), chemokine (C-C motif) ligand 28 (CCL28), v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), adenylate kinase 2 (AK2), myelin basic protein (MBP), and fatty acid desaturase 1 (FADS1), wherein the expression level of the biomarker(s) in the sample is decreased relative to a reference expression level, denoting increased suicidality; or   wherein when the subject is female, and the panel of biomarkers comprises:   (i) erythrocyte membrane protein band 4.1 like 5 (EPB41L5), HtrA serine peptidase 1 (HTRA1), deleted in primary ciliary dyskinesia homolog (DPCD), general transcription factor IIIC (GTF3C3), period circadian clock 1 (PERI), pyridoxal-dependent decarboxylase domain containing 1 (PDXDC1), kelch-like family member 28 (KLHL28), ubiquitin interaction motif containing 1 (UIMC1), sorting nexin family member 27 (SNX27), glutamate receptor ionotropic kainate 2 (GRIK2), wherein the expression level of the biomarker(s) in the sample is increased relative to a reference expression level, denoting increased suicidality; or   (ii) phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3), aldehyde dehydrogenase 3 family member A2 (ALDH3A2), ARP3 actin-related protein 3 homolog (yeast) (ACTR3), B-cell CLL (BCL2), MOB kinase activator 3B (MOB3B), casein kinase 1 alpha 1 (CSNK1A1), La ribonucleoprotein domain family member 4 (LARP4), zinc finger protein 548 (ZNF548), prolylcarboxypeptidase (angiotensinase C) (PRCP), and solute carrier family 35 (adenosine 3′-phospho 5′-phosphosulfate transporter) member B3 (SLC35B3), wherein the expression level of the biomarker(s) in the sample is decreased relative to a reference expression level, denoting increased suicidality;   determining a reference score for the panel, obtained in a clinically relevant population identifying a difference between the score of the panel of biomarker(s) in the sample and the reference score of the panel of biomarker(s);   and identifying the subject having suicidality based on the difference between the biomarker panel score of the subject relative to the biomarker panel score of reference; and   administering to the subject identified as having suicidality a specific therapeutic drug(s) to treat suicidality, based on the specific biomarkers that are changed in the subject wherein the therapeutic drug (s) is selected from:   (i) a group of psychiatric treatments: ketamine and other dissociants, lithium and other mood stabilizers, clozapine, chlorpromazine, prochlorperazine, and other antipsychotics, selegeline, fluoxetine, trimipramine, and other antidepressants, docosahexaenoic acid and other omega-3 fatty acids, and combinations thereof; or   (ii) a group of new method of use/repurposed drugs consisting of: tocilizumab, tenoxicam, ramifenazone, and other anti-inflammatories; betulin, dl-alpha tocopherol, hesperidin, calcium folinate, harpagoside, rilmenidine, harman, homatropine, diphenhydramine, pirenperone, asiaticoside, adiphenine, metformin, chlorogenic acid, verapamil, metaraminol, yohimbine, trimethadione, and combinations thereof.   
     
     
         22 . The method of  claim 21 , wherein before the step of generating the biomarker panel score, each biomarker is given a weighted coefficient, wherein the weighted coefficient is related to the importance of said each biomarker in assessing and predicting suicide risk. 
     
     
         23 . The method of  claim 21 , wherein the biological sample is a peripheral tissue sample or a fluid. 
     
     
         24 . The method of  claim 21 , wherein biomarker expression level measures RNA or protein of the biomarker in the biological sample. 
     
     
         25 . The method of  claim 21 , wherein the subject is male, and the drug is selected based on the specific biomarkers that are changed in expression in the subject, and is selected from the group consisting of: thiamine, homatropine, vitexin, ergocalciferol, tropicamide, (−)-atenolol, haloperidol, spaglumic acid, and combinations thereof. 
     
     
         26 . The method of  claim 21 , wherein the subject is female, and the drug is selected based on the specific biomarkers that are changed in expression in the subject, and is selected from the drug group consisting of: mifepristone, lansoprazole, nafcillin, betulin, and combinations thereof. 
     
     
         27 . The method of  claim 21 , wherein the subject has a psychiatric disorder selected from the group consisting of: bipolar disorder, major depressive disorder, schizophrenia, schizoaffective disorder, anxiety disorders, post-traumatic stress disorder, and combinations thereof. 
     
     
         28 . A method of assessing and mitigating suicidality in a subject in need thereof, comprising: calculating an Up-Suicide Scorebased on the equation:
   (Biomarker Panel Score)+(Suicidality Risk Score)+(Mood Score)+(Anxiety Score)=Up-Suicide Score;   wherein the Biomarker Panel Score is obtained as per the method of  claim 21 ;   wherein the Suicidality Risk Score is calculated by   (i) summing the binary results of the individual items in the CFI-S scale;   wherein a yes/present answer generates a score of 1 and a no/absent answer generates a score of zero; and   (ii) dividing the summed score by the number of items answered and multiplying by 100; wherein the individual items in the CFI-S scale are: lack of coping skills (cracks under pressure); dissatisfaction with present life; lack of hope for the future; current substance abuse; acute stresses: losses, grief; chronic stress: lack of positive relationships, social isolation; acute stress: rejection, history of excessive extroversion and impulsive behaviors (including rage, anger, physical fights, seeking revenge); acute/severe medical illness, pain; lack of children; Gender: Male; Personally knowing somebody who committed suicide; Psychiatric illness diagnosed and treated; past history of suicidal acts/gestures; Age: Older>60 or Younger<25; History of abuse: physical, sexual, emotional, neglect; History of command hallucinations of self-directed violence; Family history of suicide in blood relatives; With poor treatment compliance; Lack of religious beliefs; History of excessive introversion, conscientiousness; Chronic stress: perceived uselessness, not feeling needed, burden to extended kin;   wherein the Mood Score is calculated by using a mood-rating scale;   wherein the Anxiety Score is calculated by using an anxiety-rating scale;   assessing the level of suicidality of the subject by comparing the subject's Up-Suicide Score to a reference Up-Suicide Score;   administering a treatment for suicidality to the subject when the subject's Up-Suicide Score is greater than a reference Up-Suicide Score; and   monitoring the subject's response to a treatment for suicidality by determining changes in the Up-Suicide Score after initiating a treatment.   
     
     
         29 . The method of  claim 28 , wherein the method further comprises receiving, in a computer system, Biomarker Panel Score, Suicidality Risk Score, Mood Score, Anxiety Score, and/or Up-Suicide Score for the subject, the computer system comprising a database, wherein the database comprises a plurality of suicidality treatment profiles. 
     
     
         30 . The method of  claim 29 , wherein the method further comprises a step of outputting from the computer system the identity of the suicidality treatment for administering to the subject. 
     
     
         31 . The method of  claim 28 , wherein a user enters the Biomarker Panel Score, Suicidality Risk Score, Mood Score, Anxiety Score, and/or Up-Suicide Score of the subject in the computer system. 
     
     
         32 . The method of  claim 28 , wherein the Biomarker Panel Score, Suicidality Risk Score, Mood Score, Anxiety Score, and/or Up-Suicide Score of the subject is received directly from equipment used in determining the subject's suicidality blood biomarker score. 
     
     
         33 . The method of  claim 28 , wherein the Biomarker Panel Score, Suicidality Risk Score, Mood Score, and Anxiety Score of the subject are z-scored prior to the calculation of the Up-Suicide Score. 
     
     
         34 . The method of  claim 28 , wherein the subject is male, the panel of biomarkers is
 (i) solute carrier family 4 (sodium bicarbonate cotransporter) member 4 (SLC4A4), cell adhesion molecule 1 CADM1, dystrobrevin alpha (DTNA), spermidine/spermine Nl-acetyl transferase 1 (SAT1), interleukin 6 (IL-6), RAS-like family 11 member B (RASL11B), glutamate receptor ionotropic kainate 2 (GRIK2), histone cluster 1 H2bo (HIST1H2BO), jun proto—oncogene (JUN), and GRB2-associated binding protein 1 (GAB1), wherein the expression level of the biomarker(s) in the sample is increased relative to a reference expression level, denoting increased suicidality; or   (ii) spindle and kinetochore associated complex subunit 2 (SKA2), CAP-GLY domain containing linker protein family, member 4 (CLIP4), kinesin family member 2C (KIF2C), kelch domain containing 3 (KLHDC3), chemokine (C—C motif) ligand 28 (CCL28), v-ets avian erythroblastosis virus E26 oncogene homolog (ERG), adenylate kinase 2 (AK2), myelin basic protein (MBP), and fatty acid desaturase 1 (FADS1), wherein the expression level of the biomarker(s) in the sample is decreased relative to a reference expression level, denoting increased suicidality; or   wherein when the subject is female, the panel of biomarkers is (i) erythrocyte membrane protein band 4.1 like 5 (EPB41L5), HtrA serine peptidase 1 (HTRA1), deleted in primary ciliary dyskinesia homolog (DPCD), general transcription factor IIIC polypeptide 3 (GTF3C3), period circadian clock 1 (PERI), pyridoxal-dependent decarboxylase domain containing 1 (PDXDC1), kelch-like family member 28 (KLHL28), ubiquitin interaction motif containing 1 (UIMC1), sorting nexin family member 27 (SNX27), glutamate receptor ionotropic kainate 2 (GRIK2), wherein the expression level of the biomarker(s) in the sample is increased relative to a reference expression level, denoting increased suicidality; or   (ii) phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3), aldehyde dehydrogenase 3 family member A2 (ALDH3A2), ARP3 actin-related protein 3 homolog (yeast) (ACTR3), B-cell CLL (BCL2), MOB kinase activator 3B (MOB3B), casein kinase 1 alpha 1 (CSNK1A1), La ribonucleoprotein domain family member 4 (LARP4), zinc finger protein 548 (ZNF548), prolylcarboxypeptidase (PRCP), solute carrier family 35 member B3 (SLC35B3), wherein the expression level of the biomarker(s) in the sample is decreased relative to a reference expression level, denoting increased suicidality.   
     
     
         35 . A method of assessing and mitigating suicidality in a subject in need thereof, comprising:
 calculating a Suicidality Risk Score by adding the score of the individual items in the CFI-S scale, wherein a yes/present answer generates a score of 1 and a no/absent answer generates a score of zero, and dividing the summed score by the number of items answered and multiplying by 100, wherein the individual items in the CFI-S scale are: lack of coping skills (cracks under pressure); dissatisfaction with present life; lack of hope for the future; current substance abuse; acute stresses: losses, grief; chronic stress: lack of positive relationships, social isolation; acute stress: rejection, history of excessive extroversion and impulsive behaviors (including rage, anger, physical fights, seeking revenge); acute/severe medical illness, pain; lack of children; Gender: Male; Personally knowing somebody who committed suicide; Psychiatric illness diagnosed and treated; past history of suicidal acts/gestures; Age: Older>60 or Younger<25; History of abuse: physical, sexual, emotional, neglect; History of command hallucinations of self-directed violence; Family history of suicide in blood relatives; With poor treatment compliance; Lack of religious beliefs; History of excessive introversion, conscientiousness; Chronic stress: perceived uselessness, not feeling needed, burden to extended kin;   assessing the level of suicidality of the subject by comparing the subject's Suicidality Risk Score to a reference Suicidality Risk Score;   administering a treatment for suicidality to the subject when the subject's Suicidality Risk Score is greater than a reference Suicidality Risk Score;   monitoring the response to a treatment of the subject by determining changes in the Suicidality Risk Score after initiation of a treatment; and   decreasing the Suicidality Risk Score by targeting with psycho-social interventions and other treatments specific items of the CFI-S that are scored as yes/present in a particular subject.   
     
     
         36 . The method of  claim 35 , wherein the method further comprises receiving, in a computer system, the scores of the individual items in the CFI-S scale or the subject's Suicidality Risk Score, the computer system comprising a database, wherein the database comprises a plurality of suicidality treatment profiles. 
     
     
         37 . The method of  claim 35 , wherein the method further comprises a step of outputting from the computer system the identity of the targeted suicidality psycho-social intervention and other treatments for administering to the subject. 
     
     
         38 . The method of  claim 36 , wherein a user enters the scores of the individual items in the CFI-S scale or subject's Suicidality Risk Score in the computer system. 
     
     
         39 . The method of  claim 36 , wherein the scores of the individual items in the CFI-S scale or the subject's Suicidality Risk Score is received directly from equipment used in determining the subject's suicidality blood biomarker score. 
     
     
         40 . The method of  claim 35 , wherein the subject's Suicidality Risk Score is z-scored along the Suicidality Risk Scores of subjects with similar Suicidality Risk Scores.