Festschrift celebrating the career of Ming T. Tsuang

Authors

  • Stephen V. Faraone,

    Corresponding author
    1. Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York
    • Correspondence to:

      Stephen V. Faraone, Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY 13210.

      E-mail: sfaraone@childpsychresearch.org

    Search for more papers by this author
  • Larry J. Seidman,

    1. Harvard Medical School, Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, Massachusetts
    Search for more papers by this author
  • Stephen Buka,

    1. Department of Epidemiology, Brown University, Providence, Rhode Island
    Search for more papers by this author
  • Jill M. Goldstein,

    1. Departments of Psychiatry and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
    2. Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, Massachusetts
    Search for more papers by this author
  • Michael Lyons,

    1. Department of Psychology, Boston University, Boston, Massachusetts
    Search for more papers by this author
  • William S. Kremen,

    1. Department of Psychiatry and Center for Behavioral Genomics, University of California, San Diego, California
    2. VA Center of Excellence for Stress and Mental Health, La Jolla, California
    Search for more papers by this author
  • Stephen J. Glatt

    1. Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York
    Search for more papers by this author

In this issue, we celebrate the career of Ming T. Tsuang, the Founding Editor of this Journal and mentor to the authors of this Editorial and to the authors of the articles that follow. Here, we provide an overview of how he has influenced psychiatry through his ideas, publications, and his mentoring of many new generations of researchers.

Today, we take for granted that psychiatric epidemiology and genetics provide a sturdy foundation for understanding the nature of psychiatric disorders. In 1957, when Ming Tsuang completed his MD degree from National Taiwan University, that was not the case. But Ming was prescient. He left Taiwan to earn a PhD in psychiatry at the Institute of Psychiatry and Doctor of Science in psychiatric genetics and epidemiology from the Faculty of Science, University of London. In London, working with Eliot Slater, one of the founders of psychiatric genetics, he published studies on the genetics of Trisomy-21 and completed his doctoral dissertation about pairs of siblings who were both hospitalized for a mental disorder [Tsuang, 1967].

THE IOWA YEARS: A TRIUMPH OF GENETIC EPIDEMIOLOGY

After completing his doctorates, he accepted a position in the Department of Psychiatry at Washington University in 1971. Then in 1972, George Winokur recruited him to the University of Iowa. Ming would put Iowa on the map of psychiatric research. He initiated the Iowa 500 study, a 30–40 year follow-up of 525 patients with schizophrenia, bipolar disorder, or major depressive disorder along with 160 surgical control subjects. He also showed the power of rigorous, case–control genetic epidemiology by studying about 3,000 of their family members—a pioneering study that set a new standard for genetic epidemiology. The Iowa 500 was groundbreaking because it was the first double-blind psychiatric study of families to use structured diagnostic interviews of all family members at a time when specific diagnostic criteria in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders and their reliability had not yet been established. Since then, systematic family studies have become fairly routine in psychiatric research. Ming was among the first to show that family studies could establish the validity of diagnoses, implicate genes in the etiology of disorders and validate milder phenotypes among family members.

The results of the Iowa 500 study demonstrated that schizophrenia and mood disorders ran in families, supporting the significance of genetic influences in these major mental illnesses [Tsuang et al., 1980]. Results from this work also contributed to establishing diagnostic criteria for psychiatry. In this way, by using and validating structured diagnostic criteria, Ming's work anticipated the Third Edition of the DSM and its subsequent revisions [Tsuang and Dempsey, 1979; Tsuang et al., 1979]. In fact, he had the foresight to understand that diagnostic criteria would change over time as we learned more about these disorders. Thus, he collected clinical data on patients and their family members who themselves did not quite meet the “criteria of the day” for the illnesses he was studying. This strategy anticipated contemporary views that psychopathological phenomena may be more validly conceptualized as continuous phenomena and may not fit neatly into a priori categories.

Ming's work with subjects lacking clear diagnoses later became known as the Iowa non-500 study. When combined with the Iowa 500 study subjects, this large family study with a representative sample of patients with major psychiatric pathology drawn from across the state of Iowa became a unique and invaluable resource. The Iowa data set would become a treasure trove for post-doctoral fellows and colleagues for many years to come [Goldstein et al., 1990, 1992, 1995; Faraone et al., 1994]. Even a young Kenneth Kendler would come to Iowa to work with these data and provide novel insights to the field [Kendler et al., 1984, 1986].

MOVING EAST: SOWING THE SEEDS FOR DISCOVERY FROM LARGE PROSPECTIVE COHORTS

The Iowa years ended in 1982 when Ming was recruited to the Brown University Program in Medicine and then in 1985 to Harvard Medical School and the Harvard School of Public Health. Three major developments ensued during his time at Brown University: (1) Laying the foundations for the large observational, longitudinal New England Family Study; (2) Expanding his multidisciplinary team and generative style of mentorship; and (3) Furthering efforts to ensure the alignment of clinical and scientific work in major psychiatry teaching centers.

Fresh from his successes with the Iowa 500 and non-500 studies, Ming recognized the great potential for psychiatric epidemiology to revitalize a landmark cohort study that had previously been conducted in Providence, RI. Discontinued 10 years earlier, Brown researchers had enrolled over 4,000 pregnant women for 7 years of follow-up as part of the Collaborative Perinatal Project (CPP). Initiated in 1959, the CPP was designed to investigate, prospectively, the prenatal and familial antecedents of pediatric, neurological, and psychological disorders of childhood using comprehensive assessments that included a wealth of family history, biological, behavioral, and neurological data. Ming introduced the idea of studying adult psychiatric outcomes within the cohort through conversations with Lewis Lipsitt who had directed the childhood assessments in Providence, and helped recruit Stephen Buka who co-designed and directed these initial follow-up efforts [Buka et al., 1988]. At the heart of the project was the seminal work of Pasamanick et al. [1956] who proposed “…a continuum of reproductive casualty extending from death [which] might descend in severity through cerebral palsy, epilepsy, mental deficiency, and perhaps even to behavior disorder.”

The first major study (the “Providence 1000”) selected from the CPP 500 infants born with moderate perinatal complications, and 500 matched comparison subjects. Using standardized psychiatric assessments, the CPP team interviewed these children as adults at a mean age of 23 years [Buka et al., 1993]. The generally null results indicated no elevated risk for psychiatric disorder in relation to perinatal complications, with two exceptions. Infants born with conditions suggestive of chronic fetal hypoxia were at marginally elevated risk for both cognitive impairment and psychotic disorders, including schizophrenia. These initial findings led to a considerable body of work over the next 25 years, with major collaborators including Stephen Buka, Jill Goldstein, and Larry Seidman [Buka et al., 1989, 1993, 1999, 2001a, 2001b; Goldstein et al., 2010]. Ongoing studies of the combined influence of perinatal complications, infections during pregnancy and family history of psychosis now include both a “high-risk” study of over 700 original CPP parents with a history of psychiatric treatment and matched unaffected comparison parents, and a nested case–control study of approximately 200 CPP offspring diagnosed with schizophrenia, bipolar disorder and other psychoses, their unaffected siblings and matched unaffected comparison subjects [see, e.g., Buka et al., 2013 in this volume]. The case–control component of the schizophrenia work resulted in the first uses of stored maternal serum samples relative to adult outcomes. This included the initial serologically based finding of elevated maternal antibodies and cytokine levels [Buka et al., 2001a, 2001b] in relation to subsequent psychosis. These schizophrenia projects now include over 1,000 CPP cohort members with and without psychotic disorders, and incorporate detailed clinical diagnostic, neuropsychological, structural, and functional imaging procedures and more [Thermenos et al., 2005; Goldstein et al., 2010; Seidman et al., 2013].

The new phase of CPP studies started by Ming eventually extended beyond psychotic disorders. What is now known as the “New England Family Study” involves the follow-up and assessment of three-generation pedigrees of members of both the Providence and Boston sites of the CPP, all investigating the role of prenatal and early life risk conditions for later psychopathology and comorbid conditions, embedded within informative family designs. Hundreds of publications and dozens of research grants resulted from Ming's initial efforts. This line of research includes novel investigations of the sequelae of maternal smoking during pregnancy using discordant sibling designs and early antecedents for nicotine dependence, other forms of substance abuse, and comorbid medical conditions. Recent work has moved from neuropsychiatric outcomes to physical conditions, with a particular emphasis on adult risks for cardiovascular disease. Other major projects have included investigations of the stability and sequelae of childhood learning disorders, attention deficit hyperactivity disorder, social determinants of depression and other psychiatric disorders, and more.

While at Brown, Ming advanced two themes that would continue throughout his professional career. First was his appreciation for methods and perspectives originating outside of psychiatry, including epidemiology, biostatistics, neuropsychology, genetics, clinical psychology, and the like—along with a readiness to support and foster the ideas and work of junior colleagues. Key junior collaborators in the mid-1980s included Buka, Faraone, Fleming, Goldstein, Kremen, Lyons, Seidman, Simpson and others, a multidisciplinary team of scientists who would remain lifelong collaborators and both enrich and greatly benefit from Ming's evolving program of research. The second theme concerned Ming's determination that clinical practice and research in psychiatry should evolve in parallel. Dr. Steven Rasmussen, Chair of Psychiatry at Brown University, recalls Ming's mastery as both scientist and clinician, enriching clinical education through scientific insights gleaned from the Iowa 500 and his other research experiences. His clinical acumen, nuanced appreciation of the multiple dimensions of psychopathology and scientific precision in approaching psychiatric disorders had a great influence on practitioners as well as researchers. Throughout his career, Ming felt that clinical research could inform clinical practice in an evolving way, which was further expressed at the Massachusetts Mental Health Center, as will be described below.

THE HARVARD YEARS: EPIDEMIOLOGY MEETS NEUROBIOLOGY AND GENETICS

Ming will be remembered at Harvard for transforming two Departments of Psychiatry that he chaired: one at the Brockton-West Roxbury VA Medical Center and the other at the Massachusetts Mental Health Center (MMHC). He also created the Harvard Institute of Psychiatric Epidemiology and Genetics and an NIMH Training Program in Psychiatric Genetics at the Harvard School of Public Health. His effectiveness as a Chair and his continued scientific productivity were recognized by Harvard Medical School by awarding him an Endowed Chair, the Stanley Cobb Professor of Psychiatry. He piloted MMHC through some very difficult years, as the venerable old building was deteriorating so badly that it was closed in November, 2003. Nevertheless, he built a tremendously vital research program while at MMHC and helped contribute to its rebirth in a new building in 2011 [Salzman et al., 2012].

After such scientific success in Iowa, many researchers might rest on their laurels. Not Ming Tsuang. During the Harvard years, he produced some of his most enduring and compelling discoveries in psychiatry, epidemiology, neurobiology and genetics. In the late 1980s, with Michael Lyons, Ming undertook the groundbreaking Harvard Twin Study of Substance Abuse. The study utilized the Vietnam Era Twin Registry that includes over 8,000 male twins who served in the United States Military at some time between 1965 and 1975. Participants were interviewed about their use of licit and illicit substances and various types of psychopathology. This project yielded powerful findings about genetic, shared environmental, and unique environmental factors on several phenotypes: the abuse of licit and illicit substances, depression, anxiety and post-traumatic stress disorder [Lyons et al., 1995, 2000, 2004, 2006, 2008; Tsuang et al., 2001]. A major contribution of the study was the demonstration that, across all categories of illicit drugs, the co-occurrence of abuse of various types of illicit drugs reflects a shared vulnerability, influenced by both genetic and environmental factors. However, some drugs were shown to have unique determinants, both genetic and environmental, that are not shared with other drugs. The Harvard Twin Study of Substance Abuse also demonstrated that the genetic influence on marijuana abuse is mediated by genetic influence on subjective effects of drugs, and that the determinants of transitions from one stage of drug use to another differ depending on which drug or which transition is examined. The interviews of over 8,000 participants in this study were used to investigate a range of disorders beyond substance use disorders. Ming, along with Michael Lyons and numerous other collaborators, utilized data from the Harvard Twin Study to produce findings about mood disorders, anxiety disorders, schizophrenia, antisocial personality disorder, post-traumatic stress disorder, and pathological gambling [Tsuang et al., 2001].

During this period, Ming also gleaned insights into the genetic underpinnings of schizophrenia by studying the unaffected relatives of patients with schizophrenia. Despite the advances made in the Iowa 500 and non-500 studies, the validity of these diagnostic categories remained uncertain due to the absence of confirmed biomarkers. It was also clear that transmission patterns for these disorders could not be explained by simple models of inheritance [Faraone and Tsuang, 1985; Goldstein et al., 1992]. Thus, in the 1980s, he began to shift his research efforts away from a focus on diagnostic categories toward biologically based phenotypes or “endophenotypes” [Faraone et al., 1995a, 1995b]. These are characteristics that mediate the effects of genes on overt symptom expression and have a plausible biological and genetic relationship to the illness. This move toward non-diagnostic phenotypes was an early harbinger of the National Institute of Mental Health's initiative to create Research Domain Criteria for psychiatric disorders.

To test this endophenotype concept, Ming's group first conducted studies of non-psychotic relatives of people with schizophrenia or with affective psychosis. Initially, the studies were conducted on adult (mean age ∼40) relatives (1988–1998), and subsequently they examined adolescent and young adult non-psychotic relatives (age 13–28; 1998–2007). These studies were funded by the National Institute of Mental Health (NIMH MERIT Award). Working closely with Larry Seidman and Steve Faraone, Ming's vision was to use dimensional measures to identify heritable, disease-specific markers of genetic risk that were presumably more proximal to underlying genotypic abnormalities than the clinical diagnosis of schizophrenia itself (“endophenotypes”) [Tsuang et al., 1993; Faraone et al., 1995a]. Ming and colleagues theorized that increased genetic risk for schizophrenia would be manifest as subtle neuropathological abnormalities in non-psychotic relatives that were similar to (but less pronounced and less widespread) than those seen in individuals with the illness. Further, because relatives are typically unmedicated, their abnormalities were free from the effects of psychiatric medication, which was not true for most studies of patients with schizophrenia. This work echoed Ming's dissertation work about siblings in the 1960s under the supervision of the famous English psychiatrist, Elliot Slater at the Maudsley Hospital's Institute of Psychiatry in London [Tsuang, 1967; Slater and Tsuang, 1968].

Ming's first foray into the study of endophenotypes was a study of neuropsychological dysfunction in patients with schizophrenia and their non-psychotic biological relatives [Faraone et al., 1995a]. He led one of the first groups to pursue this line of research. At the time he began this work, the dominant view in psychiatry was that neuropsychological dysfunction in schizophrenia was related to the disease itself [Seidman, 1983]. But Ming felt strongly that such impairments could be associated with the vulnerability to the illness and that this could be a fruitful line of research to pursue. Ultimately, his findings that the relatives of patients with schizophrenia manifested similar (albeit milder) cognitive deficits provided strong reasons for re-evaluating that view. Indeed, these results suggested that neuropsychological deficits were a sub-clinical expression of schizophrenia caused by the same genetic influences as schizophrenia [Kremen et al., 1992, 1995, 1997]. With such findings having been widely replicated, the consensus in the field has changed dramatically, with the dominant viewpoint now being that neuropsychological deficits are among the core features of the illness.

The initial work in adult relatives, many of whom had passed through the peak age of risk of psychosis, showed that neurocognitive and neuroimaging abnormalities were associated with familial vulnerability, independent of the psychotic state and associated confounding factors, as summarized in a number of reviews [Kremen et al., 1994; Seidman, 1997; Tsuang et al., 1999b; Faraone et al., 2001; Seidman and Wencel, 2003; Seidman et al., 2003; Gur et al., 2007; MacDonald et al., 2009]. Later investigations focused on the further characterization of these abnormalities in younger relatives prior to or within the age of risk for psychosis (ages 13–28), those at “genetic high risk” (GHR) [Seidman et al., 2006]. The rationale for this later work was stimulated by a shift in the field toward early intervention and prevention of schizophrenia, and study of the psychosis prodrome. This was further supported by a number of innovative and productive studies of premorbid neurocognitive, social and behavioral indicators of risk in biological offspring or relatives of persons with psychosis [Niemi et al., 2003; Keshavan et al., 2005, 2010; Stone et al., 2005; Glatt et al., 2006; Agnew-Blais and Seidman, 2013].

In 1990, working closely with Larry Seidman and Jill Goldstein, Ming extended this approach to the study of brain abnormalities based on structural and functional magnetic resonance imaging. These studies have been critical for the understanding of schizophrenia, including hippocampal volume reductions in non-psychotic relatives of individuals with schizophrenia [Seidman et al., 2002], volumetric abnormalities across the cortex [Goldstein et al., 1999], and even sex differences in hypothalamic volume that were present in non-psychotic relatives [Goldstein et al., 1999, 2007]. In functional brain imaging studies, his team identified brain activity deficits in non-psychotic relatives of schizophrenia patients, including in prefrontal and cingulate cortices and thalamic regions during performance of an auditory verbal working memory task [Thermenos et al., 2004]. These data showed that structural and functional brain abnormalities were also putative endophenotypes for schizophrenia.

In subsequent research, Ming extended his work on endophenotypes and helped move the field closer to studies of early intervention and prevention by reconceptualizing Paul Meehl's notion of the liability for schizophrenia (“schizotaxia”) as an explicit syndrome with explicit diagnostic criteria. He also proposed that psychosis, long the hallmark of schizophrenia, was the least specific component of the illness [Tsuang et al., 2000]. He defined schizotaxia as a sub-syndromal manifestation of schizophrenia-associated deficits that includes the presence of neuropsychological deficits, social dysfunction, and negative symptoms [Faraone et al., 2001]. He showed that roughly a third of the non-psychotic relatives of schizophrenia patients exhibit “schizotaxia,” strongly suggesting that it identifies potential carriers of the risk genes for schizophrenia. These relatives were ideal candidates for etiologic research because they were not medicated or chronically hospitalized [Tsuang et al., 1999a, 2002]. In essence, the study of these individuals provided a valuable window into the etiology of the illness because they made possible the study of genetic vulnerability for schizophrenia unconfounded by the illness features of schizophrenia such as medication use and chronicity. Identifying valid sub-syndromal conditions also raised the tantalizing possibility of early identification, which in turn, suggested the possibility of early intervention or even prevention.

In a remarkable innovation, Ming developed the schizotaxia treatment protocol, which was a proof-of-concept clinical trial for testing drugs that would be potentially useful for preventive interventions. Because these relatives had schizotaxia, but not a formal DSM diagnosis of a schizophrenia-related disorder, the idea of administering medications to them was controversial. However, this work held the great promise of achieving real progress in efforts toward early identification and prevention. Moreover, all those who volunteered for this open-label trial were, in fact, experiencing some subjective distress and wished to try the medication. The trial showed that a very low dose of an atypical antipsychotic medication decreased neuropsychological impairment and negative symptoms among schizotaxic adult relatives of patients with schizophrenia. This study was the first of its kind, and its results, when considered in conjunction with clinical data, provide concurrent validity for schizotaxia as a meaningful and useful entity that may have some place in subsequent reformulations of nosologic boundaries in psychiatry [Tsuang et al., 1999a, 2002; Stone et al., 2001].

In a subsequent study, Ming confirmed the validity of schizotaxia through a cluster analysis in a larger sample of relatives of patients with schizophrenia [Stone et al., 2012]. He also showed that a low dose of an atypical antipsychotic medication improved performance on tests of cognition using in a double blind, placebo-controlled protocol [Tsuang et al., 1999c]. These pioneering efforts broadened our perspective on potential preventive measures that may be used to combat the emergence of schizophrenia.

Although the tools of epidemiology served him well, Ming, working closely with Steve Faraone, was quick to recognize that the tools of molecular genetics would be needed to unravel the complex genetics of psychiatric disorders. He was a founding member of the National Institute of Mental Health (NIMH) Molecular Genetics Initiative [Faraone et al., 1996, 1998, 1999] and Chair of the Veteran's Administration's Cooperative Genetic Linkage Study of Schizophrenia [Faraone et al., 2002, 2005]. With the NIMH collaborative group he developed the Diagnostic Interview for Genetic Studies, which has been translated into many languages and remains the gold standard interview for genetic studies of schizophrenia and mood disorders [Faraone et al., 1996]. This early work, at the dawn of the psychiatric molecular genetics era would, eventually, teach the field that genes for psychiatric disorders had very small effects and that more sensitive approaches, such as genome wide association and sequencing studies would be needed to make progress.

THE UCSD YEARS: FROM GENOMICS TO TRANSCRIPTOMICS

After the Harvard years (1985–2003), Ming was recruited to the faculty in Psychiatry at the University of California, San Diego (UCSD) where he was awarded the rank of University Professor at the University of California, the highest honor that can be bestowed on faculty by the Board of Regents. Since 1960, only 38 faculty in the entire University of California system have been awarded this title.

At USCD, Ming established a new Center for Behavioral Genomics (CBG) to serve as the springboard for the next phase of his research which, while continuing to pursue genetic risk factors, now shifted increasingly toward the pursuit of biomarkers. At the CBG, working with Steve Glatt, he initiated some of the earliest transcriptomic studies of neuropsychiatric disorders. This line of work aims to unravel the neurobiological basis for these disorders and establish biologically meaningful diagnostic subtypes that can be detected by reproducible biological tests.

In the first study of its kind in psychiatry, Ming used microarray technology to determine the patterns of blood-based gene expression among individuals with schizophrenia, bipolar disorder, and normal comparison subjects, and he was able to differentiate gene expression patterns among all three groups [Tsuang et al., 2005]. By examining gene expression patterns in blood cells, rather than the traditional method of examining postmortem tissue, he established an innovative framework for antemortem biologically based diagnosis of major mental illnesses. The results from this early study were extremely promising, as it documented a high level of sensitivity and specificity of gene-expression markers for these various conditions [Glatt et al., 2005; Tsuang et al., 2005]. In addition, because the large numbers of genes comprising these microarrays were relatively unselected (i.e., not influenced by assumptions about the disease), they determined the best predictors of each state in an unbiased manner. Subsequently, he advanced this peripheral-blood-based biomarker strategy to identify predictors of treatment response in schizophrenia, to identify the risk state for schizophrenia in unaffected first-degree relatives of schizophrenic patients, and to profile the susceptibility to other disorders, such as autism and post-traumatic stress disorder [Glatt et al., 2009a, 2009b, 2011a, 2011b, 2012, 2013].

In an innovative research study, in collaboration with the ongoing Marine Resilience Study, Ming is exploring gene expression profiles as a method to predict outcomes (specifically the emergence of PTSD, depression, and anxiety) in US Marines exposed to traumatic events. Working closely with Bill Kremen and Steve Glatt, he is hopeful that this information will help prevent and/or protect individuals from the devastating impact of PTSD. Ming is also engaged in the Vietnam Era Twin Study of Aging (VETSA), which is led by his former mentees Michael Lyons at Boston University and Bill Kremen and Carol Franz in the CBG at UCSD. The VETSA projects are longitudinal behavioral genetic studies of cognitive and brain aging (see, e.g., Kremen et al. and Lyons et al. in this volume). They are “direct descendants” of Ming's Harvard Twin Study, with all participants having been randomly selected from the earlier Harvard study.

Continuing his collaborations with Steve Glatt and Steve Faraone, Ming has continued his pursuit of genetic risk factors for schizophrenia. His team has been ascertaining schizophrenia patients and their families in Taiwan for the past decade with the collaboration of Wei Jen Chen and Hai-Gwo Hwu. Genetic analyses of these families have contributed a great deal toward our understanding of the genetic architecture of the disorder [Faraone et al., 2006; Glatt et al., 2009a]. Most recently, Ming has used DNA samples from 1,800 of these families in one of the largest known family-based exome-sequencing efforts to date, revealing numerous de novo mutations present in the affected probands which were not present in either of their parents. This work adds to a growing body of literature identifying the importance of genetic—but not necessarily inherited—variants on risk for the disorder.

The long-term aims of Ming's research programs have been to identify risk and protective factors for mental illnesses, construct models that accurately predict risk for these disorders, and devise and implement strategies for preventing their emergence. His recent efforts to find stable biomarkers for schizophrenia, bipolar disorder, depression, PTSD, autism, and other major mental disorders, as well as for the risk of these illnesses among unaffected relatives, will not only aid gene discovery but may help revolutionize the nosologic approach toward psychiatric disorders. The problems of accuracy and specificity in formulating psychiatric diagnoses, prediction of treatment response, course and outcome, and risk identification for early intervention and prevention efforts are long-standing issues that have not been satisfactorily resolved with traditional methods of investigation and analysis. Ming's approaches to these problems have moved the discussion about diagnostic criteria from the realm of phenomenology to the realm of biology. He now has the opportunity to make substantial progress in this direction through the multidisciplinary resources he has assembled in the CBG.

MOVING FORWARD: A STRATEGY FOR THE FUTURE

Despite all he has accomplished, Ming continues, as he always has, to look towards and plan for the future, believing as Pasteur did that fortune favors the prepared mind. Today Ming is laying the groundwork for several avenues of investigation that promise to continue pushing the boundaries of the possible. A survey of Ming's pilot studies and developmental research reads like a list of the top scientific challenges of the past decade: stem cell biology, whole-genome sequencing, RNA regulatory mechanisms, non-coding variation and missing heritability. Both for the purpose of biomarker research and for studying the effects of implicated genetic variants on neurobiological functions, Ming is working with Gene Yeo, Ph.D., and other collaborators at UCSD toward profiling the transcriptomes and functionality of induced pluripotent stem cells and differentiated neurons originally obtained from living human subjects. Ming also is actively applying both DNA and RNA sequencing methods in his studies. Ming's genome-wide linkage studies, GWASs, candidate-gene association studies, and even his early exome-sequencing studies of schizophrenia have left him optimistic that much more of the missing heritability of schizophrenia (and other neuropsychiatric disorders, for that matter) will be found by surveying intronic and intergenic regions of the genome; thus, he has begun whole-genome sequencing of a number of trios from his study of schizophrenia in Taiwan. And Ming is now routinely applying RNA sequencing in the pursuit of blood-based biomarkers for numerous disorders, including in the context of the North American Prodrome Longitudinal Study of Schizophrenia (NAPLS) within which he has already completed microRNA sequencing and is working toward additional sequencing for coding transcripts and other non-coding transcripts such as long intergenic (linc)RNAs. Beyond such “hard” bench science, Ming has also shown heightened interest recently in studying aspects of our nature not so often explored scientifically. For example, his involvement in the VETSA Twin study of aging has opened many interesting avenues into the genetic basis of non-pathological traits, such as successful aging, coping styles, and even forgiveness and spirituality. Lacking a long history of research, these topics are in need of rigorous appraisal from a genetic epidemiologic framework, which Ming is uniquely poised to implement.

CELEBRATING THE CONTRIBUTIONS OF MING T. TSUANG

Ming's career has been celebrated in many ways. He was elected to top medical and scientific organizations (e.g., the Institute of Medicine of the U.S. National Academy of Sciences, the Academia Sinica of Taiwan, and the Royal College of Psychiatrists of the United Kingdom). He was awarded the Rema Lapouse Award for Mental Health Epidemiology, presented by the Mental Health, Epidemiology and Statistics Sections of the American Public Health Association; the Stanley Dean Award for Basic Research in Schizophrenia, American College of Psychiatrists; the Lifetime Achievement Award from the International Society of Psychiatric Genetics, the Lieber Prize for Outstanding Achievement in Schizophrenia Research from the Brain and Behavior Research Foundation, and the Gold Medal Award from the Society of Biological Psychiatry.

In addition to this extraordinary list of awards acknowledging Ming's scientific achievements, we also celebrate Ming's generativity. More than half a century ago Eric Erikson coined the term generativity to describe ones' concerns for supporting and guiding the next generation. One expression of Ming's generativity takes the form of awards that have been made possible by the generous contributions of Ming and his wife Snow. These include: (1) the Ming Tsuang Lifetime Achievement Award, given to a scientist in the International Society of Psychiatric Genetics who has made a significant contribution to the advancement of the field of psychiatric genetics; (2) the Harvard Award in Psychiatric Epidemiology and Biostatistics, given to an individual whose lifelong career contributions have significantly advanced those fields; and (3) the Tsuang Financial Aid Fund to support epidemiology students.

The other dimension of Ming's generativity is his mentorship and guidance. Here, we wish to express the enduring gratitude of the many students, fellows, and junior colleagues who have benefited from his knowledge, wisdom, and guidance and will continue to do so for many years to come. Indeed, the guidance and opportunities Ming provided have fostered the development of many successful independent careers. We see this journal edition as a tribute to his many accomplishments by his mentees and colleagues, a compendium of psychiatric knowledge to which he has contributed that will be passed down to the next generation of scientists and clinicians and mental health policy makers.

Ancillary