Publications

2014
Torous J, Chan SR, Yee-Marie Tan S, Behrens J, Mathew I, Conrad EJ, Hinton L, Yellowlees P, Keshavan M. Patient Smartphone Ownership and Interest in Mobile Apps to Monitor Symptoms of Mental Health Conditions: A Survey in Four Geographically Distinct Psychiatric Clinics. JMIR Ment Health 2014;1(1):e5.Abstract
BACKGROUND: Despite growing interest in mobile mental health and utilization of smartphone technology to monitor psychiatric symptoms, there remains a lack of knowledge both regarding patient ownership of smartphones and their interest in using such to monitor their mental health. OBJECTIVE: To provide data on psychiatric outpatients' prevalence of smartphone ownership and interest in using their smartphones to run applications to monitor their mental health. METHODS: We surveyed 320 psychiatric outpatients from four clinics around the United States in order to capture a geographically and socioeconomically diverse patient population. These comprised a state clinic in Massachusetts (n=108), a county clinic in California (n=56), a hybrid public and private clinic in Louisiana (n=50), and a private/university clinic in Wisconsin (n=106). RESULTS: Smartphone ownership and interest in utilizing such to monitor mental health varied by both clinic type and age with overall ownership of 62.5% (200/320), which is slightly higher than the average United States' rate of ownership of 58% in January 2014. Overall patient interest in utilizing smartphones to monitor symptoms was 70.6% (226/320). CONCLUSIONS: These results suggest that psychiatric outpatients are interested in using their smartphones to monitor their mental health and own the smartphones capable of running mental healthcare related mobile applications.
Haller CS, Padmanabhan JL, Lizano P, Torous J, Keshavan M. Recent advances in understanding schizophrenia. F1000Prime Rep 2014;6:57.Abstract
Schizophrenia is a highly disabling disorder whose causes remain to be better understood, and treatments have to be improved. However, several recent advances have been made in diagnosis, etiopathology, and treatment. Whereas reliability of diagnosis has improved with operational criteria, including Diagnostic and Statistical Manual of Mental Disorders, (DSM) Fifth Edition, validity of the disease boundaries remains unclear because of substantive overlaps with other psychotic disorders. Recent emphasis on dimensional approaches and translational bio-behavioral research domain criteria may eventually help move toward a neuroscience-based definition of schizophrenia. The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence. Such etiopathological understanding has motivated a renewed search for novel pharmacological as well as psychotherapeutic targets. Addressing the core features of the illness, such as cognitive deficits and negative symptoms, and developing hypothesis-driven early interventions and preventive strategies are high-priority goals for the field. Schizophrenia is a severe, chronic mental disorder and is among the most disabling disorders in all of medicine. It is estimated by the National Institute of Mental Health (NIMH) that 2.4 million people over the age of 18 in the US suffer from schizophrenia. This illness typically begins in adolescence and derails the formative goals of school, family, and work, leading to considerable suffering and disability and reduced life expectancy by about 20 years. Treatment outcomes are variable, and some people are successfully treated and reintegrated (i.e. go back to work). Despite the effort of many experts in the field, however, schizophrenia remains a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan. Comprehensive treatment entails a multi-modal approach, including psychopharmacology, psychosocial interventions, and assistance with housing and financial sustenance. Research to date suggests a network of genetic, neural, behavioral, and environmental factors to be responsible for its development and course. This article aims to summarize and explain recent advancements in research on schizophrenia, to suggest how these recent discoveries may lead to a better understanding and possible further development of effective therapies, and to highlight the paradigm shifts that have taken place in our understanding of the diagnosis, etiopathology, and treatment.
Torous J, Friedman R, Keshavan M. Smartphone ownership and interest in mobile applications to monitor symptoms of mental health conditions. JMIR Mhealth Uhealth 2014;2(1):e2.Abstract
BACKGROUND: Patient retrospective recollection is a mainstay of assessing symptoms in mental health and psychiatry. However, evidence suggests that these retrospective recollections may not be as accurate as data collection though the experience sampling method (ESM), which captures patient data in "real time" and "real life." However, the difficulties in practical implementation of ESM data collection have limited its impact in psychiatry and mental health. Smartphones with the capability to run mobile applications may offer a novel method of collecting ESM data that may represent a practical and feasible tool for mental health and psychiatry. OBJECTIVE: This paper aims to provide data on psychiatric patients' prevalence of smartphone ownership, patterns of use, and interest in utilizing mobile applications to monitor their mental health conditions. METHODS: One hundred psychiatric outpatients at a large urban teaching hospital completed a paper-and-pencil survey regarding smartphone ownership, use, and interest in utilizing mobile applications to monitor their mental health condition. RESULTS: Ninety-seven percent of patients reported owning a phone and 72% reported that their phone was a smartphone. Patients in all age groups indicated greater than 50% interest in using a mobile application on a daily basis to monitor their mental health condition. CONCLUSIONS: Smartphone and mobile applications represent a practical opportunity to explore new modalities of monitoring, treatment, and research of psychiatric and mental health conditions.
Torous J. Digital psychiatry in Asia. Asian J Psychiatr 2014;10:1-2.
Torous J. Mobile technology and global mental health. Asian J Psychiatr 2014;10:69-70.
Torous J, Keshavan M, Gutheil T. Promise and perils of digital psychiatry. Asian J Psychiatr 2014;10:120-2.
From Pharmacovigilance to Clinical Care Optimization.
Celi LA, Moseley E, Moses C, Ryan P, Somai M, Stone D, Tang K-O. From Pharmacovigilance to Clinical Care Optimization. Big Data 2014;2(3):134-141.Abstract

In order to ensure the continued, safe administration of pharmaceuticals, particularly those agents that have been recently introduced into the market, there is a need for improved surveillance after product release. This is particularly so because drugs are used by a variety of patients whose particular characteristics may not have been fully captured in the original market approval studies. Even well-conducted, randomized controlled trials are likely to have excluded a large proportion of individuals because of any number of issues. The digitization of medical care, which yields rich and accessible drug data amenable to analytic techniques, provides an opportunity to capture the required information via observational studies. We propose the development of an open, accessible database containing properly de-identified data, to provide the substrate for the required improvement in pharmacovigilance. A range of stakeholders could use this to identify delayed and low-frequency adverse events. Moreover, its power as a research tool could extend to the detection of complex interactions, potential novel uses, and subtle subpopulation effects. This far-reaching potential is demonstrated by our experience with the open Multi-parameter Intelligent Monitoring in Intensive Care (MIMIC) intensive care unit database. The new database could also inform the development of objective, robust clinical practice guidelines. Careful systematization and deliberate standardization of a fully digitized pharmacovigilance process is likely to save both time and resources for healthcare in general.

Halpern Y, Choi Y, Horng S, Sontag D. Using Anchors to Estimate Clinical State without Labeled Data. AMIA Annu Symp Proc 2014;2014:606-15.Abstract
We present a novel framework for learning to estimate and predict clinical state variables without labeled data. The resulting models can used for electronic phenotyping, triggering clinical decision support, and cohort selection. The framework relies on key observations which we characterize and term "anchor variables". By specifying anchor variables, an expert encodes a certain amount of domain knowledge about the problem while the rest of learning proceeds in an unsupervised manner. The ability to build anchors upon standardized ontologies and the framework's ability to learn from unlabeled data promote generalizability across institutions. We additionally develop a user interface to enable experts to choose anchor variables in an informed manner. The framework is applied to electronic medical record-based phenotyping to enable real-time decision support in the emergency department. We validate the learned models using a prospectively gathered set of gold-standard responses from emergency physicians for nine clinically relevant variables.
Sands DZ, Wald JS. Transforming health care delivery through consumer engagement, health data transparency, and patient-generated health information. Yearb Med Inform 2014;9:170-6.Abstract
OBJECTIVE: Address current topics in consumer health informatics. METHODS: Literature review. RESULTS: Current health care delivery systems need to be more effective in the management of chronic conditions as the population turns older and experiences escalating chronic illness that threatens to consume more health care resources than countries can afford. Most health care systems are positioned poorly to accommodate this. Meanwhile, the availability of ever more powerful and cheaper information and communication technology, both for professionals and consumers, has raised the capacity to gather and process information, communicate more effectively, and monitor the quality of care processes. CONCLUSION: Adapting health care systems to serve current and future needs requires new streams of data to enable better self-management, improve shared decision making, and provide more virtual care. Changes in reimbursement for health care services, increased adoption of relevant technologies, patient engagement, and calls for data transparency raise the importance of patient-generated health information, remote monitoring, non-visit based care, and other innovative care approaches that foster more frequent contact with patients and better management of chronic conditions.
Baron JM, Dighe AS, Arnaout R, Balis UJ, Black-Schaffer SW, Carter AB, Henricks WH, Higgins JM, Jackson BR, Kim J, Klepeis VE, Le LP, Louis DN, Mandelker D, Mermel CH, Michaelson JS, Nagarajan R, Platt ME, Quinn AM, Rao L, Shirts BH, Gilbertson JR. The 2013 symposium on pathology data integration and clinical decision support and the current state of field. J Pathol Inform 2014;5:2.Abstract
BACKGROUND: Pathologists and informaticians are becoming increasingly interested in electronic clinical decision support for pathology, laboratory medicine and clinical diagnosis. Improved decision support may optimize laboratory test selection, improve test result interpretation and permit the extraction of enhanced diagnostic information from existing laboratory data. Nonetheless, the field of pathology decision support is still developing. To facilitate the exchange of ideas and preliminary studies, we convened a symposium entitled: Pathology data integration and clinical decision support. METHODS: The symposium was held at the Massachusetts General Hospital, on May 10, 2013. Participants were selected to represent diverse backgrounds and interests and were from nine different institutions in eight different states. RESULTS: The day included 16 plenary talks and three panel discussions, together covering four broad areas. Summaries of each presentation are included in this manuscript. CONCLUSIONS: A number of recurrent themes emerged from the symposium. Among the most pervasive was the dichotomy between diagnostic data and diagnostic information, including the opportunities that laboratories may have to use electronic systems and algorithms to convert the data they generate into more useful information. Differences between human talents and computer abilities were described; well-designed symbioses between humans and computers may ultimately optimize diagnosis. Another key theme related to the unique needs and challenges in providing decision support for genomics and other emerging diagnostic modalities. Finally, many talks relayed how the barriers to bringing decision support toward reality are primarily personnel, political, infrastructural and administrative challenges rather than technological limitations.
Mohammad F, Theisen-Toupal JC, Arnaout R. Advantages and limitations of anticipating laboratory test results from regression- and tree-based rules derived from electronic health-record data. PLoS One 2014;9(4):e92199.Abstract
Laboratory testing is the single highest-volume medical activity, making it useful to ask how well one can anticipate whether a given test result will be high, low, or within the reference interval ("normal"). We analyzed 10 years of electronic health records--a total of 69.4 million blood tests--to see how well standard rule-mining techniques can anticipate test results based on patient age and gender, recent diagnoses, and recent laboratory test results. We evaluated rules according to their positive and negative predictive value (PPV and NPV) and area under the receiver-operator characteristic curve (ROC AUCs). Using a stringent cutoff of PPV and/or NPV≥0.95, standard techniques yield few rules for sendout tests but several for in-house tests, mostly for repeat laboratory tests that are part of the complete blood count and basic metabolic panel. Most rules were clinically and pathophysiologically plausible, and several seemed clinically useful for informing pre-test probability of a given result. But overall, rules were unlikely to be able to function as a general substitute for actually ordering a test. Improving laboratory utilization will likely require different input data and/or alternative methods.
Crotty BH, Mostaghimi A. Confidentiality in the digital age. BMJ 2014;348:g2943.
Safran C. Reuse of clinical data. Yearb Med Inform 2014;9:52-4.Abstract
OBJECTIVES: To provide an overview of the benefits of clinical data collected as a by-product of the care process, the potential problems with large aggregations of these data, the policy frameworks that have been formulated, and the major challenges in the coming years. METHODS: This report summarizes some of the major observations from AMIA and IMIA conferences held on this admittedly broad topic from 2006 through 2013. This report also includes many unsupported opinions of the author. RESULTS: The benefits of aggregating larger and larger sets of routinely collected clinical data are well documented and of great societal benefit. These large data sets will probably never answer all possible clinical questions for methodological reasons. Non-traditional sources of health data that are patient-sources will pose new data science challenges. CONCLUSIONS: If we ever hope to have tools that can rapidly provide evidence for daily practice of medicine we need a science of health data perhaps modeled after the science of astronomy.
Fischer SH, David D, Crotty BH, Dierks M, Safran C. Acceptance and use of health information technology by community-dwelling elders. Int J Med Inform 2014;83(9):624-35.Abstract
OBJECTIVES: With the worldwide population growing in age, information technology may help meet important needs to prepare and support patients and families for aging. We sought to explore the use and acceptance of information technology for health among the elderly by reviewing the existing literature. METHODS: Review of literature using PubMed and Google Scholar, references from relevant papers, and consultation with experts. RESULTS: Elderly people approach the Internet and health information technology differently than younger people, but have growing rates of adoption. Assistive technology, such as sensors or home monitors, may help 'aging in place', but these have not been thoroughly evaluated. Elders face many barriers in using technology for healthcare decision-making, including issues with familiarity, willingness to ask for help, trust of the technology, privacy, and design challenges. CONCLUSIONS: Barriers must be addressed for these tools to be available to this growing population. Design, education, research, and policy all play roles in addressing these barriers to acceptance and use.
Fischer SH, Tjia J, Reed G, Peterson D, Gurwitz JH, Field TS. Factors associated with ordering laboratory monitoring of high-risk medications. J Gen Intern Med 2014;29(12):1589-98.Abstract
BACKGROUND: Knowledge about factors associated with provider ordering of appropriate testing is limited. OBJECTIVE: To determine physician factors associated with ordering recommended laboratory monitoring tests for high-risk medications. METHODS: Retrospective cohort study of patients prescribed a high-risk medication requiring laboratory monitoring in a large multispecialty group practice between 1 January 2008 and 31 December 2008. Analyses are based on administrative claims and electronic medical records. The outcome is a physician order for each recommended laboratory test for each prescribed medication. Key predictor variables are physician characteristics, including age, gender, specialty training, years since completing training, and prescribing volume. Additional variables are patient characteristics such as age, gender, comorbidity burden, whether the medication requiring monitoring is new or chronic, and drug-test characteristics such as inclusion in black box warnings. We used multivariable logistic regression, accounting for clustering of drugs within patients and patients within providers. RESULTS: Physician orders for laboratory testing varied across drug-test pairs and ranged from 9% (Primidone-Phenobarbital level) to 97% (Azathioprine-CBC), with half of the drug-test pairs in the 85-91% ordered range. Test ordering was associated with higher provider prescribing volume for study drugs and specialist status (primary care providers were less likely to order tests than specialists). Patients with higher comorbidity burden and older patients were more likely to have appropriate tests ordered. Drug-test combinations with black box warnings were more likely to have tests ordered. CONCLUSIONS: Interventions to improve laboratory monitoring should focus on areas with the greatest potential for improvement: providers with lower frequencies of prescribing medications with monitoring recommendations and those prescribing these medications for healthier and younger patients; patients with less interaction with the health care system are at particular risk of not having tests ordered. Black box warnings were associated with higher ordering rates and may be a tool to increase appropriate test ordering.
Patient-to-physician messaging: volume nearly tripled as more patients joined system, but per capita rate plateaued.
Crotty BH, Tamrat Y, Mostaghimi A, Safran C, Landon BE. Patient-to-physician messaging: volume nearly tripled as more patients joined system, but per capita rate plateaued. Health Aff (Millwood) 2014;33(10):1817-22.Abstract

Patients want to be able to communicate with their physicians by e-mail. However, physicians are often concerned about the impact that such communications will have on their time, productivity, and reimbursement. Typically, physicians are not reimbursed for time spent communicating with patients electronically. But under federal meaningful-use criteria for information technology, physicians can receive a modest incentive for such communications. Little is known about trends in secure e-mail messaging between physicians and patients. To understand these trends, we analyzed the volume of messages in a large academic health system's patient portal in the period 2001-10. At the end of 2010, 49,778 patients (22.7 percent of all patients seen within the system) had enrolled in the portal, and 36.9 percent of enrolled patients (8.4 percent of all patients) had sent at least one message to a physician. Physicians in the aggregate saw a near tripling of e-mail messages during the study period. However, the number of messages per hundred patients per month stabilized between 2005 and 2010, at an average of 18.9 messages. As physician reimbursement moves toward global payments, physicians' and patients' participation in secure messaging will likely increase, and electronic communication should be considered part of physicians' job descriptions.

2013
Blanco R, Blanco D, Quintana Y, Escobar X, Rengifo CE, Osorio M, Gutiérrez Z, Lamadrid J, Cedeño M, Frómeta M, Carr A, Rengifo E. Immunoreactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Primary Lymphoid Tumors and Lymph Node Metastasis. Patholog Res Int 2013;2013:920972.Abstract
The reactivity of the 14F7 Mab, a highly specific IgG1 against N-glycolyl GM3 ganglioside (NeuGcGM3) in normal tissues, lymphomas, lymph node metastasis, and other metastatic sites was assessed by immunohistochemistry. In addition, the effect of chemical fixation on the 14F7 Mab staining using monolayers of P3X63Ag.653 cells was also evaluated. Moreover, the ability of 14F7 to bind NeuGcGM3 ganglioside inducing complement-independent cytotoxicity by a flow cytometry-based assay was measured. The 14F7 Mab was reactive in unfixed, 4% paraformaldehyde, 4% formaldehyde, and acetone fixed cells. Postfixation with acetone did not alter the localization of NeuGcGM3, while the staining with 14F7 Mab was significantly eliminated in both cells fixed and postfixed with methanol but only partially reduced with ethanol. The staining with 14F7 Mab was evidenced in the 89.2%, 89.4%, and 88.9% of lymphomas, lymph node metastasis, and other metastatic sites, respectively, but not in normal tissues. The treatment with 14F7 Mab affected both morphology and membrane integrity of P3X63Ag.653 cells. This cytotoxic activity was dose-dependent and ranged from 24.0 to 84.7% (10-1000  μ g/mL) as compared to the negative control. Our data could support the possible use of NeuGcGM3 as target for both active and passive immunotherapy against malignancies expressing this molecule.
Quintana Y, Patel AN, Arreola M, Antillon FG, Ribeiro RC, Howard SC. POND4Kids: a global web-based database for pediatric hematology and oncology outcome evaluation and collaboration. Stud Health Technol Inform 2013;183:251-6.Abstract
The Pediatric Oncology Network Database, (www.pond4kids.org, POND), is a secure, web-based, multilingual pediatric hematology/oncology database created for use in countries with limited resources to meet various clinical data management needs including cancer registration, delivery of protocol-based care, outcome evaluation, and assessment of psychosocial support programs. Established as a part of the International Outreach Program at St. Jude Children's Research Hospital in Memphis, Tennessee, POND serves as a tool for oncology units to store patient data for easy retrieval and analysis and to achieve uniform data collection to facilitate meaningful comparison of information among centers. Launched in 2003, POND now has 233 sites registered with over 1,000 users in 66 countries. However, adoption and usage of POND varies widely among sites. This paper reviews some of the challenges to developing a global collaborative clinical platform based on the experiences of developing POND. The paper also presents a case study of POND use in Guatemala, where the Guatemalan National Oncology Unit (UNOP) has developed extensive internal and external global collaborations using POND.
Blanco R, Quintana Y, Blanco D, Cedeño M, Rengifo CE, Frómeta M, Ríos M, Rengifo E, Carr A. Tissue Reactivity of the 14F7 Mab Raised against N-Glycolyl GM3 Ganglioside in Tumors of Neuroectodermal, Mesodermal, and Epithelial Origin. J Biomark 2013;2013:602417.Abstract
The expression of N-glycolylneuraminic acid forming the structure of gangliosides and/or other glycoconjugates (Hanganutziu-Deicher antigen) in human has been considered as a tumor-associated antigen. Specifically, some reports of 14F7 Mab (a highly specific Mab raised against N-glycolyl GM3 ganglioside) reactivity in human tumors have been recently published. Nevertheless, tumors of epithelial origin have been mostly evaluated. The goal of the present paper was to evaluate the immunohistochemical recognition of 14F7 Mab in different human tumors of neuroectodermal, mesodermal, and epithelial origins using an immunoperoxidase staining method. Samples of fetal, normal, and reactive astrocytosis of the brain were also included in the study. In general, nontumoral tissues, as well as, low-grade brain tumors showed no or a limited immunoreaction with 14F7 Mab. Nevertheless, high-grade astrocytomas (III-IV) and neuroblastomas, as well as, sarcomas and thyroid carcinomas were mostly reactive with 14F7. No reaction was evidenced in medulloblastomas and ependymoblastomas. Our data suggest that the expression of N-glycolyl GM3 ganglioside could be related to the aggressive behavior of malignant cells, without depending on the tumor origin. Our data could also support the possible use of N-glycolyl GM3 as a target for both active and passive immunotherapies of malignancies expressing this molecule.
Armstrong K, Keating NL, Landry M, Crotty BH, Phillips RS, Selker HP. Academic general internal medicine: a mission for the future. J Gen Intern Med 2013;28(6):845-51.Abstract
After five decades of growth that has included advances in medical education and health care delivery, value cohesion, and integration of diversity, we propose an overarching mission for academic general internal medicine to lead excellence, change, and innovation in clinical care, education, and research. General internal medicine aims to achieve health care delivery that is comprehensive, technologically advanced and individualized; instills trust within a culture of respect; is efficient in the use of time, people, and resources; is organized and financed to achieve optimal health outcomes; maximizes equity; and continually learns and adapts. This mission of health care transformation has implications for the clinical, educational, and research activities of divisions of general internal medicine over the next several decades.

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