Clinical database of the CYP-guides trial: An open data resource on psychiatric hospitalization for severe depression.

CYP-GUIDES (Cytochrome Psychotropic Genotyping Under Investigation for Decision Support) is a randomized controlled trial (RCT) of pharmacogenetic decision support in the psychotropic treatment of hospitalized patients with major depressive disorder or severe depression. Patients were treated according to their CYP2D6 functional status or empirically and compared for both their Length of Stay (LOS, primary outcome) at the hospital and Re-Admission Rate (RAR, secondary outcome) 30 days after discharge. The trial was conducted at the Institute of Living (Hartford Hospital, Hartford CT). CYP2D6 genotyping was implemented to infer the functional status of the CYP2D6 enzyme and classify it as sub-normal, normal or supra-normal. The electronic medical record (EMR) transmitted to the physician the indicated drug prescribing guidance. During the RCT, 1500 patients were recruited and 1459 genotyped for CYP2D6. A 1:2 randomization assigned 477 patients to standard therapy (Group S) and 982 to genetically-guided therapy (Group G). In Group S, standard empiric treatment was indicated for all patients. In Group G, medications primarily metabolized by the CYP2D6 enzyme were proscribed for patients with sub- or supra-normal CYP2D6 function. The clinical course, therapeutic guidance, and drug treatment for each patient are being published in this article and deposited in Mendeley Data. These data should be valuable to assess the impact of clinical decision support on utilization of psychiatric resources for treatment of severe depression requiring hospitalization.

a b s t r a c t CYP-GUIDES ( Cy tochrome P sychotropic G enotyping U nder I nvestigation for De cision S upport ) is a randomized controlled trial (RCT) of pharmacogenetic decision support in the psychotropic treatment of hospitalized patients with major depressive disorder or severe depression. Patients were treated according to their CYP2D6 functional status or empirically and compared for both their Length of Stay (LOS, primary outcome) at the hospital and Re-Admission Rate (RAR, secondary outcome) 30 days after discharge. The trial was conducted at the Institute of Living (Hartford Hospital, Hartford CT). CYP2D6 genotyping was implemented to infer the functional status of the CYP2D6 enzyme and classify it as sub-normal, normal or supra-normal. The electronic medical record (EMR) transmitted to the physician the indicated drug prescribing guidance. During the RCT, 1500 patients were recruited and 1459 genotyped for CYP2D6 . A 1:2 randomization assigned 477 patients to standard therapy ( Group S ) and 982 to genetically-guided therapy ( Group G ). In Group S, standard empiric treatment was indicated for all patients. In Group G , medications primarily metabolized by the CYP2D6 enzyme were proscribed for patients with sub-or supra-normal CYP2D6 function.
The clinical course, therapeutic guidance, and drug treatment for each patient are being published in this article and deposited in Mendeley Data . These data should be valuable to assess the impact of clinical decision support on utilization of psychiatric resources for treatment of severe depression requiring hospitalization.
© 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license.
( http://creativecommons.org/licenses/by/4.0/ ) Specifications Table   Subject Psychiatric hospitalization and severe depression Specific subject area Psychotropic medication administration to inpatients with major depressive disorder or severe depression at a psychiatric hospital Type of data

Value of the data
• This database describes the clinical course of 1500 inpatients with major depressive disorder or severe depression at a tertiary psychiatric hospital. • Clinical investigators, healthcare administrators and actuaries will be able to assess resource utilization during psychiatric hospitalization. • The database could be analyzed for covariates and specific sub-cohorts defined by ethnicity, drug prescription or length of stay.
• Drug prescription patterns are well documented based on number of different psychotropics as well as total number of administrations. • Identifiers are provided for the psychiatrists treating the patients, which could enable evaluation of physician behavior. • The specific therapeutic guidance provided for each patient is identified to support trial on the use of clinical decision support in psychiatric hospitalization.

Data description
The dataset in this article provides basic demographic characteristics, along with information regarding trial group assignment, length of stay, 30-day readmission, and medication administration during the hospital stay.
Data have been de-identified in accordance with the standards of the Privacy Rule of the Health Insurance Portability and Accountability Act (HIPAA), utilizing the Safe Harbor method [1] . In accordance with this method, the data do not contain the 18 personal identifiers specified, and no subjects are included with an age above 89. A unique code (ID) has been assigned to each subject as specified by the de-identification implementation standards. These data are longer considered individually identifiable health information as there is no reasonable basis to believe that the information can be used to identify an individual.
Data in the total dataset are described as follows: ID -Unique identification number assigned to each patient who was enrolled in the trial. GENDER -Male or female. AGE -The age, in years, of each patient at the time of enrollment. RACE/ETHNICITY -Race was self-reported by the patient from a system database, which included "White", "Black", "Latino", and "Other/Unknown" as options. Therefore, this column is referred to as "Race/Ethnicity". DIAGNOSIS -The diagnosis given upon admission to the hospital, which was used by the trial coordinator to evaluate each patient for inclusion in the trial. MD -Alphabetic code assigned to each hospital physician who cared for the patients in the trial. ASSIGNMENT -Patients were randomly assigned to Group S or Group G in a 1:2 ratio. Patients in Group S received standard care, whereas patients in Group G had their psychotropic prescriptions guided by their CYP2D6 functional status. ELECTRONIC MEDICAL RECORD (EMR) -During the course of the trial, 2 platforms for EMR were employed: the Clinical Evaluation and Monitoring System (C) and the Epic R (E) EMR. The first 856 patients were recruited and followed under CEMS, and the subsequent 644 under Epic R . LOS -Length of Stay (in hours) at the psychiatric hospital (IOL), defined and calculated as the date/time of discharge minus the date/time of admission. RAR -30 day Re -Admission Rate. A "1" denotes that the patient was readmitted at least once during the thirty days after they were discharged. A "0" denotes no evidence of a readmission during the same time period could be found. COLUMNS A through AD -Coded columns for the medications and the number of administrations for each during the hospital stay. Each Column represents a different medication from the formulary as prescribed and comprised of the following drugs: Amitriptyline, Aripiprazole, Asenapine, Bupropion, Chlorpromazine, Citalopram, Clomipramine, Clonidine, Doxepin, Duloxetine, Escitalopram, Fluoxetine, Fluphenazine, Fluvoxamine, Guanfacine, Haloperidol, Imipramine, Lithium, Methylphenidate, Mirtazapine, Nortriptyline, Olanzapine, Paliperidone, Perphenazine, Quetiapine, Risperidone, Sertraline, Trazodone, Venlafaxine, Ziprasidone. A key for these columns is included in the dataset. Each number corresponds to the number of times that the given medication was administered to the patient while in the hospital.  Demographics. Demographics for the total cohort and database of the CYP-GUIDES trial are shown in Table 1 .

Trial design
In the CYP-GUIDES study, a prospective RCT, outcomes in patients with major depressive disorder or severe depression were compared among those treated according to CYP2D6 functional status versus those treated following standard, empiric psychotropic selection.
Methodology for the trial has been detailed in a published report [3] , and the findings have been reported for the total cohort [4] . The RCT was registered in ClinicalTrials.gov as Pharmacogenetic Decision Support IT System for Psychiatric Hospitalization: RCT (CYP-GUIDES) and assigned identifier NCT 02120729 in the registry [5] .

Trial site
The Institute of Living (IOL) at Hartford Hospital was the single site where the RCT was conducted. A clinical coordinator trained by the psychiatric nursing staff and by the investigators consented all patients. A self-identified ethnicity was provided by each patient at admission. CYP2D6 genotyping and functional phenotyping was performed onsite at Hartford Hospital by the clinical Laboratory of Personalized Health (LPH).

Inclusion/Exclusion criteria
The following were criteria for Inclusion: (a) age 18 y or older, (b) all men or women not pregnant or nursing, (c) admission to the Institute of Living for major depressive disorder or severe depression [6] , (d) capacity to understand and comply with the trial's requirements, procedures and protocol. The following were criteria for Exclusion: (a) all children and adolescents, (b) admission to the hospital 30 days prior to current admission, (c) diagnoses or history of dementia, Alzheimer's disease, chronic kidney disease, hemorrhagic stroke, subarachnoid hemorrhage, ischemic stroke or surgery within 6 weeks, (d) current participation in any other clinical trial for investigational drugs or devices.

Protection of human subjects
Informed consent was developed and approved by the Hartford Hospital Institutional Review Board (Protocol RUAN004090HE). The informed consent listed and explained to patients the risks and benefits of their participation in the trial. A Data Safety Monitoring Board (DSMB) was established to monitor safety and efficacy of the intervention among all participants and to review data or request statistical analyses as needed for its recommendations.

Randomization
We randomized assignment to Group S (Standard care) or Group G (Genetically guided) independently of CYP2D6 genotype. ISAAC, a 64 bit shift MD5 program frequently used for encryption, was adapted for the random assignment. Both patient and physician were blinded to Group S versus Group G assignment.

Electronic medical record (EMR)
Two platforms for EMR were employed during the course of the study. Clinical Evaluation and Monitoring System (CEMS) was embedded within the Behavioral Health Care Information System for 25 years at IOL [ 7 , 8 ] and used from April 2014 to 19 August 2016 for 856 patients. The Epic R EMR was deployed at IOL as part of organization-wide medical informatics integration by the Hartford Healthcare Corporation and employed thereafter for the subsequent 644 patients.

Outcomes
Length of Stay (LOS) [ 9 , 10 ] was the primary outcome. Re-Admission Rate (RAR) 30 days after discharge [ 11 , 12 ] was the secondary outcome. Exact calculation of LOS in hours for each patient was enabled by the EMR's timestamps for admission and discharge. To obtain RAR, the EMR was searched for readmissions to the IOL in the 30-day post-discharge period.

Genetic information
The Metabolic Reserve (MR) index was developed in 2011 by our group from a study of 1199 psychiatric referrals to derive a quantitative, composite CYP450 functional phenotype [13] . It was then adapted to CYP2D6 only and validated in a preliminary clinical study of 149 psychiatric inpatients in 2013 [14] . MR is calculated by adding the functional score of each of the 2 CYP2D6 alleles for each patient.
MR was then implemented when the CYP-GUIDES RCT began in 2014 to derive the CYP2D6 enzymatic function from the patient's CYP2D6 diplotype. MR values were grouped to index a patient's CYP2D6 functional phenotype to 3 categories: (a) Sub-functional (MR 0.0, 0.5 or 1.0), (b) Functional (MR 1.5, 2.0 or 2.5), and (c) Supra-functional (MR 3.0 or 3.5).

Therapeutic guidances
Physicians were blinded to CYP2D6 functional and to Group S versus Group G assignment. Instead, drug guidance charts were provided to physicians for the antidepressants, antipsychotics, and stimulants commonly used at IOL.
There were 3 drug guidance charts [3] with all drugs colorized according to their suitability for the patient's CYP2D6 functional status: (a) Evergreen, with all drugs colorized green, advising prescription as usual; ( b) Christmas Tree , with CYP2D6 major substrate drugs colorized red, alerting proscription, and the others colorized green; and (c) Traffic Light, with CYP2D6 minor substrate drugs also colorized yellow, alerting caution.
Evergreen was indicated for all patients in Group S. Evergreen was also indicated for patients in Group G with normal CYP2D6 function (MR 1.5, 2.0 or 2.5). Christmas Tree was indicated for patients in Group G with abnormal CYP2D6 function (MR 0.5, 1.0 or 3.0). Traffic Light was indicated for patients in Group G with extreme CYP2D6 function (MR 0.0 or 3.5).