Psychiatric genetic counseling: A mapping exercise

1 INTRODUCTION

Genetic counseling has been defined as the process of helping people “understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease” (Resta et al., 2006). This process “integrates the following: (1) Interpretation of family and medical histories to assess the chance of disease occurrence, relapse, or recurrence in those already affected with a psychiatric disorder and those who are unaffected but at increased risk based on family history; (2) Education about inheritance, testing, management, prevention, resources, and research; (3) Counseling to promote informed choices and adaptation to the risk or condition” (Resta et al., 2006).

In the context of various conditions, genetic counseling has been shown to increase understanding of etiology, and the implications of genetic testing, and to promote patient autonomy in choosing screening or treatment options facilitating a meaningful informed consent for testing (Austin, 2010; Broadstock, Michie, & Marteau, 2000; Roche, 2006). It can also help patients and families manage stigma and undercut unwarranted optimism or pessimism about the genetic findings (Friesen, Lawrence, Brucato, Girgis, & Dixon, 2016; Tsuang, Stone, & Faraone, 2001).

Psychiatric genetics has a long and troubled history (Fraser, 1974; Gottesman & Bertelsen, 1996). An overwhelming body of evidence spanning the last 60 years (Kendler, Gallagher, Abelson, & Kessler, 1996; Kessler et al., 2007; Sullivan et al., 2018) shows that psychiatric illnesses are highly heritable (and therefore have a genetic component), with for example, schizophrenia and bipolar disorder having an estimated heritability of 60–85% (Parnas et al., 1993; Sham et al., 1994) and 70–85%, respectively (Papadimitriou et al., 2003; Prescott & Gottesman, 1993; Wray & Gottesman, 2012). But, it is only from efforts over the past 10 years by the Psychiatric Genomics Consortium that focus has shifted from studying heritability indirectly to directly using genome-wide genetic data. Psychiatric illnesses are complex disorders arising from heterogeneous combinations of multiple genetic variants interacting with the environment (Cardno & Owen, 2014; Insel & Collins, 2003; Merikangas & Risch, 2003; Wray & Gottesman, 2012). Individually, most common genetic variants have effect sizes that are too small to be deterministic but, by interacting with each other (Ruderfer et al., 2018; Sullivan et al., 2018) and with environmental factors (Uher, 2014), they place an individual at a higher or lower risk (Pestka, 2003; Schmitt, Malchow, Hasan, & Fallkai, 2014). As well however, rarer genetic variations including copy number variants, can also contribute and have larger effects. As efforts continue to create genetic risk scores that are clinically useful (Sullivan et al., 2018) so must the transition of appropriate dissemination services.

Accompanying our growing understanding of the complex nature of major psychiatric disorders is a parallel need to assist patients and families in understanding the mechanisms, and adapting to the implications of psychiatric disorders, including risk factors that might contribute to illness occurrence in families (Austin & Honer, 2005; Duffy, Grof, Robertson, & Alda, 2000; Finn & Smoller, 2006; Jenkins & Arribas-Ayllon, 2016). Studies have consistently shown that well over half of individuals with bipolar disorder and schizophrenia, as well as their close relatives, are interested in education and counseling about genetics (DeLisi & Bertisch, 2006; Lyus, 2007; Quaid, Aschen, Smiley, & Nurnberger, 2001; Schulz et al., 1982). Therefore, there is a growing need, driven by patients, for appropriate counseling about the genetic contributions to psychiatric illness.

Genetic counseling for psychiatric disorders is conceptually identical to that provided for other complex disorders. It can provide patients and their family members with information and support regarding the etiology of illness, recurrence and relapse risks in those already affected with the disorder, risks to those who are unaffected, family planning, and management (Finn & Smoller, 2006).

Theoretical interest in applying genetic counseling in the context of psychiatric disorders has had a relatively long history (DeLisi & Bertisch, 2006; Finn & Smoller, 2006; Fraser, 1974; Hodgkinson, Murphy, O'Neill, Brzustowicz, & Bassett, 2001; Kumar, 1968; Lyus, 2007; Papadimitriou et al., 2003; Reveley, 1985; Stancer & Wagener, 1984; Tsuang et al., 2001) and many positive outcomes have been posited. As with other disorders, even in the absence of any genetic test, PGC provides a forum for exploring and promoting the understanding of the illness, facilitates decision-making, and adaptation to the illness (Finn & Smoller, 2006; Hunter, Hippman, Honer, & Austin, 2010). More recently, empirical studies (Austin & Honer, 2008; Costain et al., 2014; Costain, Esplen, Toner, Hodgkinson, & Bassett, 2014; Hippman et al., 2016; Inglis, Koehn, McGillivray, Stewart, & Austin, 2015) have shown that PGC is beneficial in improving knowledge about etiology and understanding causes, in alleviating emotional distress and guilt and in improving self-efficacy and empowerment both for individuals with psychiatric disorders and their family members (Moldovan, Pintea, & Austin, 2017).

Despite the important benefits that PGC offers for patients, the role of genetic counselors in psychiatry has, to date, been limited. In an effort to map opportunities and challenges related to providing patients with this important service, we explore the development of psychiatric genetic counseling services globally. Given that the research and practice in this area is developing, we decided to favor an exploratory-descriptive approach and addressed our aims from a phenomenological perspective. The goal of our inquiry was to describe and understand the current state of PGC by using purposive sampling and inviting contributions from collaborators whose efforts in this community are known (i.e., participants in PGC courses organized in the UK and US, authors of PGC articles, members of PGC consortia). Specifically, contributions were solicited by email (by RM, KM, and JA) from all remaining authors on this article, each of whom was asked to provide perspective from the context of their own country based on a guideline looking at four key issues: (a) defining PGC; (b) describing typical PGC services; (c) describing availability of PGC training; (d) providing contextual information about the provision of PGC that would allow deeper understanding of PGC in their country (see Supporting Information). The 16 narrative responses were compiled, and were analyzed to extract key themes (identified by consensus between RM, KM, and JA), and generate a consolidated overarching narrative. The product of this process was circulated to all contributors for their comments, feedback, verification, and endorsement. The resulting consolidated narrative that we present here highlights the main similarities and differences in terms of how PGC is conceptualized, types of services provided and training available, and discusses country- and regional- specific issues (e.g., healthcare systems, culture).

2 REGIONAL PERCEPTIONS AND AWARENESS OF PSYCHIATRIC GENETIC COUNSELING

Knowledge about PGC among healthcare professionals, patients, families, and the general public was limited in most of the countries from which we consulted experts. In countries where genetic counseling is not yet an established profession, such as Italy, Spain, Portugal, or Romania, for example (where the specialty is in the process of being recognized and structured), the unfamiliarity among these groups was not exclusive to psychiatric genetic counseling but applied to genetic counseling in general (Pàmpols et al., 2016; Paneque et al., 2016). In these regions, there is an overall misunderstanding about the scope of genetic counseling and most patients and professionals are not able to confidently correctly define it.

Indeed, awareness of genetic counseling among patients, families and healthcare providers is not complete or widespread even in countries where genetic counseling has been established as a profession for decades, such as the US, Canada, the UK, or Australia (Leeming, 2013; Maio, Carrion, Yaremco, & Austin, 2013; Ormond et al., 2018; Paneque et al., 2016; Riesgraf, Veach, MacFarlane, & LeRoy, 2015), and misperceptions about its purpose remain (Amy & Rowlands, 2018; Gershon & Alliey-Rodriguez, 2018; Harper, 2017).

Therefore, it is unsurprising that within this context, the awareness of PGC is low, and perceptions of what it might entail vary among patients, families, and other healthcare providers. Experts reported that in their regions, PGC is often thought of as being synonymous with psychoeducation, broadly the same as generic counseling for psychiatric disorders, or only relevant to people in families with a known or extensive psychiatric family history. Clearly, PGC is a personalized process aimed at helping people with a personal or family history of psychiatric illness understand its etiological mechanisms as a critical component and use counseling strategies to adapt to psychological and familial implications of the disease. Yet, even among healthcare providers familiar with specialist PGC services, awareness of the full scope of what the service entails seems to be limited (Leach et al., 2016).

3 PROVIDERS AND RECIPIENTS OF PSYCHIATRIC GENETIC COUNSELING AROUND THE WORLD

Clinical genetics services were initially established with a view to serving families living with single gene disorders or chromosome syndromes (e.g., Down syndrome), and then evolved to assist individuals dealing with complex conditions for which genetic testing became clinically available (e.g., cardiomyopathies or breast and ovarian cancer). Within this context, the experts consulted, reported that clinicians in their countries do not typically consider psychiatric disorders to be appropriate indications for referral to genetic counseling services. Currently, if PGC is considered at all, it is most likely to be considered for families living with genetic syndromes that have defined psychiatric manifestations (e.g., 22q11 deletion syndrome), or families with a strong family history of serious psychiatric disorders such as schizophrenia or when a patient raises questions about psychiatric disorders in relation to family planning/childbearing decisions. However, anecdotally, when patients are receiving care in a genetics clinic for a different reason, some do ask about the possibility of “inherited” mental illness, particularly when discussing their family history.

PGC is gradually developing globally, with countries in various stages of development. Therefore, access to state-of-the art services is clearly uneven around the world. In some regions PGC is established as a specialist service (e.g., Canada) or as part of research projects (e.g., the UK, Romania) while in others it is just emerging (e.g., Portugal, Sweden, Russia) (see Table 1 for a summary).

At present, PGC is not routinely offered to individuals and families impacted by disorders such as schizophrenia, bipolar disorder, or depression anywhere in the world. Even in Canada, where a specialist PGC clinic has been established, only a few psychiatrists have embraced referring to the clinic as part of routine practice.

It seems that in most countries where we consulted experts, such as Portugal, Spain, Italy, Poland, Israel, South Africa, or Australia, a family history of psychiatric disorders is only discussed in clinical genetics settings if raised by a patient during intake or if uncovered by the counselor during a session for another indication, but it is rarely the reason for the primary referral.

In Norway or France, for example, there would have to be a strong family history of psychiatric disorders or other signs of genetics contributors to disease, to support a referral to clinical genetics. Consequently, support to this patient group is more likely provided by psychiatrists, apart from situations where a psychiatric disorder presents as part of a genetic syndrome. In this context, support is provided by the clinical genetic services.

In Sweden PGC is occasionally offered to families explicitly requesting this service, often related to a pregnancy (either planned or ongoing). The counseling is provided by a physician—generally a psychiatrist or the medical doctor overseeing the pregnancy. Professionals might occasionally refer families to the genetics department in which case a clinical geneticist will provide the counseling. The emphasis is in most cases risk evaluation and information and genetic testing is unlikely to be offered. It is not a service routinely offered therefore there is no clear referral pathway.

PGC services are underdeveloped in the United States compared to other specialty areas in the genetic counseling field. There are several reasons for the dearth of PGC providers/clinics. While there are over 4,000 masters-level trained genetic counselors in the United States, and many in highly specialized roles, there are currently no full-time providers of PGC services. While some genetic counselors provide counseling to patients who report personal or family histories of mental illness after presenting for unrelated indications, it is rare for a patient to be referred specifically for PGC. The misconception that genetic counseling is only valuable when a genetic test exists for a specific condition limits referral for formal PGC. In addition, many clinical genetics clinics have long waiting lists and do not encourage referrals for psychiatric indications. While the multifactorial etiology of mental illness may be addressed by mental health counselors, psychologists, and psychiatrists, formal PGC is rarely taking place. Many genetic counselors have a low level of self-rated competency to provide PGC and agree that their training had not prepared them to address psychiatric disorders (Zhou et al., 2014). Some graduate genetic counseling training programs are attempting to address this by adding PGC coursework.

At present, PGC is being offered as part of two research projects in Romania and the UK. Patients affected by Schizophrenia, Schizoaffective, and Bipolar Disorder and Major Depressive disorder are offered free sessions on a research basis trying to establish the acceptability and benefits to patients of such a service. However, no specific PGC centers are active and no formal referral or reimbursement pathways are currently available outside the research projects.

Currently PGC is rarely offered as a specialist service anywhere in the world. The world's first specialist PGC clinic opened in Vancouver, Canada in 2012 (http://www.bcmhsus.ca/our-services/genetic-counselling-(the-adapt-clinic). This clinic provides PGC to individuals and families living in BC who have a history of any psychiatric disorder (whether it has been formally diagnosed or not). Counseling services are provided by Masters-level trained, board certified genetic counselors, and patients often seek this service to better understand etiology of illness, ways to protect mental health (either from a recurrence or a first episode) and/or chances for the disorder in other family members (such as children). Appointments are offered in person, via videoconferencing and over the phone to better serve those living further from the clinic or who have difficulty leaving their home due to poor mental health (Inglis et al., 2015). PGC has demonstrated that it increases patients' self-efficacy and empowerment (Inglis et al., 2015), and leads to gains in patients' knowledge and accuracy of risk perception (Hippman et al., 2016).

4 TRAINING IN PSYCHIATRIC GENETIC COUNSELING

With exceptions for some training programs in the US and Canada, PGC training is not formally or routinely offered as part of the MSc in genetic counseling nor as part of medical schools and independent continuous education courses (e.g., Australia, Italy, Israel, France, Norway, Philippines, Portugal, Spain, South Africa, Sweden, Russia, UK). On the rare occasions where PGC lectures or modules are included in undergraduate or postgraduate programs for clinical specialists and geneticists, they are mainly aimed at providing trainees with knowledge and skills for situations where psychiatric symptoms are associated with genetic syndromes.

However, there is increasing awareness by healthcare professionals for genetic counseling in psychiatry (Smoller et al., 2018) and its relevance to this discipline (Zhou et al., 2014), suggesting an increasing demand for continuing education. This is particularly important given the limited understanding of genetics in the general public (Paiva, Silva, Severo, Moura-Ferreira, & Lunet, 2017).

There are several opportunities for training in PGC. The Translational Psychiatric Genetics Group regularly provide lectures on PGC for the genetic counseling masters programs in Canada and in the United States and they also mentor genetic counselors who have a particular interest in PGC or have a case with a psychiatric focus. Additionally, over the last 3 years, they have provided a five 2-day intensive courses on PGC for healthcare providers working in the field, which have shown positive outcomes in terms of knowledge and self-efficacy (McGhee, Inglis, Morris, & Austin, in prep).

5 CONTEXTUAL INFORMATION ABOUT THE PROVISION OF PGC IN SPECIFIC COUNTRIES/REGIONS

Although there are countless genetics and psychiatry departments, and some excellent genetic counseling services based around the world, PGC services are essentially lacking.

The current growing demand for PGC as a specialist service challenges the available numbers of genetic counselors in a context where most healthcare budgets are constrained. Therefore, it is understandable that most genetics departments do not routinely offer PGC and referral pathways are rare. However, misconceptions about the value and usefulness of genetic counselors in this domain may also play a role. The concept that genetic counseling is only required or indicated when a genetic test is available is pervasive and contributes to the fact that PGC is deprioritized in relation to prenatal or oncogenetics applications. Misconstructions about mental health and stigma are also key factors that influence if, when and how psychiatric disorders are discussed in clinical genetics settings. Stigma can prevent people with psychiatric diagnoses from seeking help (for example, in the general public the most acceptable psychiatric diagnosis in Poland, like many other countries, is depression) and can interfere with healthcare professionals' provision of services (Feret, Conway, & Austin, 2011; Martin et al., 2012; Morris, Inglis, Friedman, & Austin, 2013).

In addition to the misconceptions about the role genetic counseling and PGC in particular play, there are other barriers to accessing PGC services. For example, in the United States, a large number of individuals with mental illness are uninsured and in any given year, less than half of Americans with mental illness receive treatment (National Institute of Mental Health [NIMH], 2017). In countries such as Spain, for example, although there is a national healthcare system, there are regulatory barriers, which can be difficult to overcome: currently there is no legal framework to support the medical geneticist specialty and no specific training is being implemented, which clearly poses a problem for many patients.

Given the limited resource of genetic counselors, in addition to already limited mental health services in countries such as South Africa, most professionals dealing with multifactorial conditions such as mental illness do not recognize the need for genetic counseling. In addition, many consider GC to only be necessary in the context of available genetic testing and do not recognize the value of the other aims associated with PGC (Robertson & Szabo, 2017). Healthcare disparities are also an issue, and the limited application of PGC has mostly been confined to the private sector where patients and families with mental illness have directly approached a genetic counselor due to their concerns about family history, typically in relation to reproductive concerns.

In many countries, the numerous competing demands on a constrained healthcare system has led to discussion regarding the development and delivery of genetics services of any kind viewed as lower priority. In the Philippines, for example, the major focus in healthcare is to alleviate the burden caused by infectious disease and to improve maternal and child health. Yet in the past decade, there has been a momentum to increase the medical genetics and genetic counseling clinical services in the country (Abad et al., 2014; Cura, 2015; Padilla & de la Paz, 2013). However, the priority areas of focus are more likely to include pediatric, metabolic, and cancer related applications rather than psychiatric.

The provision of genetic counseling services differs among various regions in terms of country-specific healthcare systems, cultural, linguistic, religious, socioeconomic, and ethical norms. Another factor that may influence the way that genetic counseling is perceived may be the remaining echoes from the eugenic practices in the 19th and 20th centuries. Despite the fact that the very first articulation of the concept of genetic counseling in 1947 explicitly emphasized the eschewing of any kind of eugenics orientation (“a kind of genetic social work without the eugenic connotations”––Reed, 1975, p. 335) and the fact that the profession has been founded on the key principle of promoting and supporting patient autonomy and empowerment, the perceived connection may still be present in some regions or groups.

Globally, country-specific worldviews and cultural practices may differ significantly from a westernized and more biomedically-focused approach to practice (Abad et al., 2014; Ormond et al., 2018; Penn & Watermeyer, 2012; Penn, Watermeyer, MacDonald, & Moabelo, 2010). Genetic counseling practices should be adapted according to context in order to meet the needs of diverse individuals and families, in a culturally competent manner (Saleh & Barlow-Stewart, 2005; Yeo et al., 2005).

6 WHAT ARE THE MAIN CHALLENGES GOING FORWARD?

The genetic counseling profession is growing globally. Access to state-of-the art services is clearly uneven around the world but there are ongoing improvements across standards of practice, training, and regulation (Abacan et al., 2018). Given the international variation in laws, health systems, and cultures, inevitably flexibility in how the profession develops and expands is undoubtedly essential. Looking specifically at PGC, several challenges have been identified by the experts we consulted.

One of the major difficulties lies in the small number of genetic counselors currently available. There are currently approximately 7,000 genetic counselors in 28 countries (Ormond et al., 2018), more than half of which are registered in the United States, and with many of them located in major academic medical centers. This is far from the recommendation of WHO to have set an expectation of 10 genetic counselors/million population (Harper, Hughes, & Raeburn, 1996). Even where they do exist, genetic counselors rarely or never see patients referred primarily for a psychiatric disorder (Hunter et al., 2010; Monaco, Conway, Valverde, & Austin, 2010), and tend to feel hesitant and unprepared to discuss family histories or psychiatric illnesses with patients (Appelbaum & Benston, 2017; Peay & McInerney, 2002) citing a lack of definitive genetic testing, a deficit in available risk assessment data, and an overall discomfort in offering psychosocial counseling for psychiatric conditions (Monaco et al., 2010). Thus, genetic counselors rarely raise issues related to psychiatric illnesses when taking family histories (Appelbaum & Benston, 2017; Peay & McInerney, 2002).

Given the prevalence of psychiatric disorders in the population, genetic counselors are very likely to see patients with these conditions themselves or those who have family members with psychiatric disorders, whether or not that is the primary indication for the counseling session (Austin et al., 2008; Peay et al., 2008). As such, genetic counselors need to be prepared to address concerns related to psychiatric conditions in their daily interactions with patients. Not only are families eager to receive PGC (Hippman et al., 2013; Quinn & Knifton, 2014); those who have experienced it indicate that they are highly satisfied with the experience and generally are unconcerned by the uncertainty inherent in risk assessment for mental illness (Costain, Esplen, Toner, Hodgkinson, & Bassett, 2014; Hippman et al., 2013), and indeed derive meaningful benefits in the form of empowerment and self-efficacy (Austin & Honer, 2008; Costain, Esplen, Toner, Hodgkinson, & Bassett, 2014; Costain, Esplen, Toner, Scherer, et al., 2014; Hippman et al., 2016; Inglis et al., 2015).

Clearly, the currently available training in PGC, both for genetic counselors in the genetics of psychiatric disorders and for psychiatrists in genetics and genetic counseling techniques, is insufficient (Appelbaum & Benston, 2017). Only a small number of training courses aimed at building genetic counselors' competence and confidence in providing PGC (Anderson & Austin, 2012; Austin et al., 2008; Peay et al., 2008; Peay & McInerney, 2002) are currently available, and genetic counselors report interest in more training in this area (Low, Dixon, Higgs, Joines, & Hippman, 2018). In fact, many studies have already highlighted the need for advanced education in the area of PGC (Anderson & Austin, 2012; Austin & Honer, 2007; Austin et al., 2008; Feret et al., 2011; Monaco et al., 2010; Peay et al., 2008; Peay & McInerney, 2002).

The experts included in our mapping exercise unanimously recognized the need for robust and consistent PGC training. Professionals around the world are building individual relationships with mental health providers and are actively working to develop formal PGC programs (e.g., California, Indiana, and Texas in the USA, Southampton, and Bournemouth in the UK, Poznan in Poland, and Cluj-Napoca in Romania).

Although people with psychiatric disorders and their families can benefit meaningfully from PGC, few currently have access to these services, as they are not provided in routine mental health settings. Current services available to this population rely heavily on local funding, staff training, and collaboration between researchers and regional healthcare services. Clearly, there is no blueprint action plan that fits all countries, as countries are at different stages in developing and implementing a comprehensive response around psychiatry, clinical genetics, genetic counseling, and mental health. Healthcare systems and service users' needs differ sensibly in terms of resources available, priorities of national healthcare systems and cultural and religious diversity.

7 CONCLUSION

Translation of psychiatric research findings into clinically meaningful services has so far been limited (Inglis et al., 2015). There is considerable interest within the psychiatric genetics community about the potential applicability of genetic testing for disorders such as schizophrenia, bipolar disorder, depression, or Attention deficit hyperactivity disorder (ADHD). Yet the main measures for a diagnostic test consist of analytic validity and clinical validity, (i.e., quality assurance and replication are essential for any future predictive test). In line with the ISPG's genetic testing statement (https://ispg.net/genetic-testing-statement/), polygenic risk scores are not currently recommended for testing of this kind for use in the clinic to identify high-risk individuals or help diagnose patients. It is true however, that a small proportion of cases in autism spectrum disorder or intellectual disability harbor important CNV findings and in some countries microarray is part of the diagnostic suite of tests. However, in the absence of clinically valid predictive tests, patients are using opportunities provided by bioinformatic platforms aimed at the public by uploading raw genomic data from DTC services to generate information about their risk for psychiatric illness. Therefore, we anticipate that PGC will expand more rapidly than future predictive tests.

Adapting existing services or designing new ones will take time and require further empirical evidence. Understandably, inevitable differences among countries are and will continue to be due to varying available resources including adequately trained professionals in delivering such services, access to experts to teach PGC courses, available budget for training programs and associated services costs. Additionally, to assume that all healthcare professionals unequivocally accept that psychiatric conditions belong to a disease model might impact how PGC is embraced in the future.

The mapping exercise revealed a number of challenges ahead and reinforced the need for a concerted global effort. Awareness and understanding of PGC is limited in most of the countries from which we consulted experts. In countries where genetic counseling is not yet an established profession, the unfamiliarity among healthcare professionals, patients, families, and the general public is not exclusive to PGC. Most professionals report not having had experience referring patients to genetic counselors (Hoop, Roberts, Green Hammond, & Cox, 2008), even though patients and families often have questions about the genetics of psychiatric disorders.

We identified a general consensus among experts from around the world that both healthcare providers and patients want better access to genetic counseling. Currently one specialist PGC clinic has been established and two others are developing PGC services in a research context. Local professionals (i.e., medical geneticists, genetic counselors, psychiatrists, and other allied health providers) often need to be creative in establishing referral pathways and set up services or clinics, those who have experience with establishing services (corresponding authors) are available to act as resources to assist other jurisdictions in their efforts. Finally, given the major technological developments (e.g., next generation sequencing technologies) and access to data available from large consortia (e.g., Psychiatric Genomics Consortium, http://www.med.unc.edu/pgc; International Consortium on Lithium Genomics, http://www.conligen.org/), a need for more widespread training in clinical genomics and PGC was recognized.

Establishing best practice recommendation and standardized training guidelines that include a good understanding of psychiatric disorders and genomics, a proficient mastery of counseling skills and ethical standards is clearly timely and essential in order to ensure quality of future PGC services. This article establishes a baseline from which progress can be tracked.

CONFLICT OF INTEREST

None.