Abstract
A major problem in schizophrenia research is the acquisition of samples of sufficient size and quality to address important scientific questions. There are several potential barriers to achieving adequate sample size. First, the psychotic experience itself may interfere with communication to such an extent that engaging the potential participant to explain the study and obtain informed consent is difficult. Second, the cognitive impairments associated with schizophrenia may interfere with decision-making capacity and thereby preclude participation. Third, negative symptoms such as apathy, anhedonia and social withdrawal can reduce motivation to participate in research protocols so that consent is not given or effective withdrawal from the study occurs through failure to keep appointments. The wide variability found in schizophrenia is itself a further barrier in that it makes achievement of homogeneous samples very difficult. Forms of variability include symptomatology, neurocognitive dysfunction, course of illness, level of disability, comorbid substance use, treatments, medication adherence and coexisting physical conditions.
Furthermore, most schizophrenia research is undertaken on clinical samples that are in current contact with mental health services. It is not clear to what extent such samples are representative of the total population of people with schizophrenia, or whether they differ significantly from those who are being treated primarily by general practitioners (GPs) or other services. Finally, given the level of uncertainty, variability and comorbidity associated with schizophrenia, and the need to formulate increasingly precise research questions, it may be necessary to have access to a relatively large pool of potential subjects in order to select appropriate samples for the questions of interest.
It is therefore proposed that schizophrenia research could be considerably advanced by the development of a large-scale database of individuals with schizophrenia in which a variety of research questions could be addressed, especially those that require large sample sizes and homogeneity on certain key dimensions of interest. Such a database would also be a useful resource for researchers wishing to obtain access to potential participants who have already indicated a willingness to participate in research projects.
Historically, large-scale accessible research databases have been predominantly in the government domain. The growth of such databases outside the government sector is still quite modest. Funding constraints, staffing requirements, ethical issues, difficulties with data collection, database design problems, security matters and long-term management are all significant obstacles to the development of large-scale research databases.
Individual research teams have traditionally constructed their own independent patient-volunteered information databases as part of a specific research programme. Such databases generally consist of samples recruited through hospital settings and therapeutic contact, but rarely include participants from other sources. Unfortunately, in psychiatric research, the relatively small sample sizes derived from these settings are subject to the problem of heterogeneity, and it is often unclear to what extent such samples are representative of the broader population of affected individuals. Hospital samples may also be associated with confounding problems related to the acute nature of the patient's illness and secondary issues related to hospitalization, medication and other treatment. The confidential nature of the information contained in small research databases means that access to this information is necessarily restricted, both to the contributors and to the wider research community. To overcome these problems, many researchers have increasingly sought collaboration with other scientists to maximize resources and strengthen research output.
Issues surrounding large-scale collaborative research database development
Several collaborative research databases of this kind have been developed in recent years providing accessible non-identifiable patient information for review and analysis (e.g. National Survey of Mental Health and Wellbeing [1], [2]). Because the data have been collected across a number of sites by trained research staff using standardized collection procedures, they are internally consistent and relatively reliable. The main limitation of these types of databases is that, while they provide increased access to data by researchers, very few are designed to provide ongoing or repeated access to the research participants by the investigators. Consequently, the information stored in them remains static and time encapsulated, and without direct access to the research sample it is impossible to develop new studies based on the established sample information. A few collaborative databases available for ongoing or repeated access do exist, comprising almost entirely non-clinical samples (e.g. Australian Twin Registry) or donor groups (e.g. Australian Kidney Donor Registry). Few psychiatric equivalents have been developed, although one example is the Psychiatric Research Database, an initiative of the Mental Health Research Institute of Victoria. This clinician-recruited patient database covers a variety of psychiatric disorders and currently includes over 250 individuals with chronic schizophrenia. There are several reasons why so few psychiatric databases exist.
It is difficult to obtain adequate numbers of individuals with psychotic illness to participate in a research database. Psychotic disorders are low in prevalence, affecting around 1% of the population [2]. The number of people with schizophrenia within a given community is therefore low, making it difficult for researchers to gain access to large numbers of potential research participants. Stigma also plays a role in this problem. Participating in psychiatric research is both a quasipublic acknowledgement, as well as a personal acknowledgement that one has a mental illness. Many individuals are therefore reluctant to be identified in this way. Investigators are thus forced to approach people who are currently receiving treatment to participate in research. But this is problematic because acutely ill individuals are not only reluctant to participate in research, but when they do they may find it difficult to participate meaningfully in clinical interviews or research trials.
In addition to recruitment issues, there are also a number of ethical considerations that impede the development of collaborative psychiatric research databases. Informed consent and mental competence to consent are two such issues. There exists a strong, yet incorrect, perception within the scientific and broader community that people with psychotic disorders are
Confidentiality and the secure storage of personal information on large-scale registers are related issues. Research databases are constrained by the same obligations and requirements concerning the collection, handling and storage of confidential information that apply to all human research activities. As such, approval is required from properly constituted research ethics committees to undertake recruitment of participants and store confidential information. However, unlike smaller individual research projects that fall under the jurisdiction of one or two local ethics committees, large-scale research databases currently need to seek approval from numerous ethics committees responsible for the recruitment domain in which the database will be operating.
Benefits of large-scale collaborative psychiatric research databases
Notwithstanding these difficulties, the development of a large-scale collaborative research database for schizophrenia has several attractions. Such a database would be able to store a large volume of participant information, providing researchers with a rich source of data that might not otherwise be accessible. In addition to being able to access non-identifiable patient data, researchers would also be able to access a pool of willing volunteers to participate in research projects. This would overcome one of the main barriers to schizophrenia research: participant recruitment. At the same time, it could provide researchers with not only a means of recruiting participants for new research initiatives, but also a way of building on existing findings utilizing the same sample. The ongoing collection of patient information could also potentially provide longitudinal data across the lifespan of individuals with schizophrenia.
Similar benefits could also extend to the research participants themselves. A large-scale collaborative psychiatric research database could provide a feedback loop for participants, giving them access to the latest research findings and keeping them abreast of the latest technologies, resources and treatment outcomes being applied to schizophrenia. It could also allow people with schizophrenia to become more active within the research process, helping to influence the research agenda to focus on areas of greatest perceived need.
The NISAD Schizophrenia Research Register
Procedures and assessment protocols
An initiative of the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), the Schizophrenia Research Register was establishedin 1998 to provide researchers with a single source of data acquired from participants with schizophrenia and to help facilitate schizophrenia research by assisting investigators with participant recruitment. The Register is a New South Wales (NSW) State-wide, medical research database for people with a clinical diagnosis of schizophrenia who are willing to consider participating in scientific research investigating the causes and treatment of schizophrenia. The Register has three primary objectives: to enable larger sample sizes and a wider representation of participants in schizophrenia research; to complement and supplement current teaching and research activities; and to help reduce the time frame for specific projects, thereby reducing the overall costs of research. The Register was modeled on other established volunteer databases, particularly the Australian NHMRC Twin Registry, the largest volunteer register in the world (with 30 000 twin pairs).
The NISAD Schizophrenia Research Register operates as a standalone, computerized (Microsoft Access) relational database, and maintains demographic and clinical information about schizophrenic individuals collected through voluntary research participation. Participants' contact details are refreshed regularly through twiceyearly newsletters and other information is updated through research participation. For security purposes, all participant information is coded and stored on the database using a password-protected system. Non-identifiable information is accessible for research purposes and for the development of new lines of investigation. Ethics committee approval for the Register to recruit and assess individuals with schizophrenia has been obtained from all the Area Health Services throughout metropolitan Sydney, rural NSW, and the Australian Capital Territory (ACT). No participant information is released to researchers without prior written consent from the participant.
There are four levels of administration within the Register: recruitment (intake), assessment, research participation and feedback.
Recruitment
The recruitment of individuals with a clinical diagnosis of schizophrenia is undertaken using a threepronged recruitment campaign. The first employs activities specifically targeting people with schizophrenia. This aspect of the campaign includes an information brochure that contains an enclosed application form. The application form requires authorization from individuals, in the form of signed consent, before their personal details (i.e. name and address) can be placed on the Register. The form then folds down into a secure self-sealing envelope with a prepaid return address. Copies of the current registration form are available throughout the public health system or by calling the toll-free telephone number (1800 639 295). An electronic version of the form is also available on the Internet (www.nisad.org.au). In addition to the brochure, there has been a corresponding poster and media campaign (i.e. television and radio commercials), as well as the establishment of a toll-free number (above), which enables State-wide access to the Register by both researchers and participants.
The second recruitment activity is focused towards health services. This involves distributing brochures and posters to all the major psychiatric hospitals, community mental health centres, accommodation services and schizophrenia support groups within NSW and the ACT. Primary care providers and psychiatrists are also targeted within this component of the campaign. The third recruitment activity targets those most likely to undertake research: the academics and clinical researchers. This strategy uses conference presentations, public forum presentations and teaching seminars to inform researchers of the unique resources available through the Register, and to encourage researchers to distribute Register recruitment brochures to the participants in their research projects.
Assessment
To ensure that registrants meet diagnostic criteria for schizophrenia, they are asked to participate in a structured assessment protocol. At this point, participants' capacity to give valid consent is evaluated and written informed consent to participate in a diagnostic interview is obtained from those capable of consenting. Those who do not meet diagnostic criteria for schizophrenia are notified by telephone and/or mail and then retained on the database, if they wish, as a potential psychiatric control. Such individuals are also asked if they are willing to have the results of their diagnostic interview made available to their treating clinician. The database also comprises a small number of non-psychiatric controls and first-degree relatives who have specifically asked to be registered on the database. The information obtained during the assessment process makes up the core information stored on the Register. The assessment protocol comprises: a measure of demographic information and medical history, including drug and alcohol usage (Schizophrenia Research Register Demographic and Clinical History Inventory: SRR-DCHI); an estimate of premorbid intelligence, namely the National Adult Reading Test (NART) [6]; a brief neuropsychological assessment, using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) [7]; a structured clinical interview to confirm the reported clinical diagnosis, using the Diagnostic Interview for Psychosis (DIP) [8]; and a rating scale of current symptoms, the Positive and Negative Syndrome Scale (PANSS) [9]. Social functioning is measured by the DIP and a general measure of functioning is provided by the Global Assessment of Functioning (GAF) scale [10]. Additional registrant information may be provided by investigators using the Register, who make available data gathered from participants in their individual projects (see below).
Research participation
Registrants are invited to participate in studies as soon as possible after registration. If registrants have not had their diagnoses confirmed as outlined above at the time of entry into a particular research project, the investigators in that project are required to confirm diagnoses using an accepted structured clinical interview. While the Register actively encourages access by research teams, this access is strictly controlled. All projects must first be approved by the relevant institutional research ethics committee(s). The scientific merit of each project is then evaluated by the Clinical Measurement Panel, which comprises experienced researchers, clinicians and clinical researchers. The Register makes all initial contact with potential participants, and only the contact details of those participants who indicate a willingness to participate in the project are provided to researchers. Each registrant selected for participation in a research project is asked to provide written informed consent to participate in the study in accordance with the research protocol of the particular project. Participation by registrants thereby remains entirely voluntary, allowing them to select the projects, if any, in which they wish to participate.
Feedback
The last stage is a feedback loop for the three groups involved, research participants, researchers and the Register. Information about research and research participation is fed back to participants through both a regular newsletter and a summary of findings by researchers at the completion of their study. As a quality assurance measure, registrants are also invited by the Register to comment on their research participation experience and, if appropriate, to make a complaint. Complaints about research participation are addressed where possible by the Clinical Measurement Panel of NISAD or, if necessary, through independent healthcare complaint avenues. As part of the feedback process, researchers are required to make an annual progress report to the Register listing information about participant involvement, articles published, any variations in approved protocol and the details of any problems or difficulties encountered. Researchers are also encouraged to provide information of relevance to the Register that has been obtained from study participants during the process of the research project. This information is added to the participants' existing data to help refresh their records and to build on the established data.
Because the Register is a relational database, part of the core information stored is research project-specific, such as the name, number and nature of projects undertaken using the facilities of the Register. Where available, the Register also includes information about the research findings, raw clinical data and the publication details of any articles derived from research linked with the Register.
Registrants' characteristics
Since its opening in 1998, the Register has recruited more than 400 people with a clinical diagnosis of schizophrenia. Just over one-fifth of the registrants have been assessed according to the protocol described above. While broadly distributed across the State, most registrants are located around the larger population centres of NSW and the ACT, particularly metropolitan Sydney (33%), the Hunter region (27%), Illawarra (7%) and Canberra (2%). Another 31% are distributed throughout smaller regional and rural areas. Based on 1-year (5–8 per 1000) prevalence rates for schizophrenia [11] it is conservatively estimated that some 32 000 adults in New South Wales and the ACT have a diagnosis of schizophrenia. Therefore, it is not unrealistic for the Register to expect to eventually recruit and maintain a cohort of around 2000 individuals with schizophrenia, a figure representing only 6% of the total estimated population with this disorder.
The self-selection process involved in volunteering to participate in research means that the majority of the individuals on the Register are likely to have relatively high functioning and motivation. This makes them a particularly valuable resource for studies requiring a close adherence to procedure (e.g. fMRI research). However, it also raises the question as to how representative samples drawn from the Register may be relative to the overall population of people with schizophrenia. A preliminary examination of this issue is described below. As a partial control for the number of statistical tests, the threshold for significance was set at p < 0.01.
Demographic comparisons
Basic demographic data for the first 400 registrants were compared with a subsample drawn from the 1999 Low Prevalence (psychotic) Disorders Study (LPDS), which recruited primarily through mental health services in four Australian States: Queensland, Victoria, Western Australian and the ACT [2], [8]. The LPDS subsample comprised 612 individuals with an ICD-10 (DIP) diagnosis of schizophrenia or schizoaffective disorder, and excluded any individuals with inpatient psychiatric admissions during the last year of 6 months or more.
Comparisons between the Register and the LPDS showed that the groups did not differ significantly from each other in age (38.74
These differences appear to reflect the communitybased recruitment strategies employed by the Register, as opposed to the predominantly mental health service focus of recruitment in the LPDS. The finding of an approximately 1:1 gender ratio for the Register sample is consistent with other estimates for this disorder [12–14] while the approximately 2:1 (male: female) ratio for the LPDS sample reflects the higher contact rates with public mental health services of males with schizophrenia. The Register's initial recruitment campaign consisted primarily of a brochure, poster and television commercial, all presented in English, which may have tended to bias the Register's sample towards Australianborn individuals (with English as a first language). Equally, the campaign was designed to emphasize the need for schizophrenia research to help find better treatments and possibly a cure, which may have encouraged married and de facto individuals to register, as a potential means of improving the long-term outcomes for their offspring.
Psychosocial and clinical comparisons
Thus far, one-fifth of the registrants have participated in structured diagnostic interviews. To examine the potential impact of recruitment source on the psychosocial and clinical characteristics of the sample, we compared the initial 50 registrants who completed the DIP (subgroup R) with selected subsamples from the LPDS, drawn from the 612 individuals identified earlier. In this instance, there were 236 LPDS participants who had been recruited through community mental health services (subgroup C) and 178 LPDS participants who had been recruited through (public) inpatient mental health services (subgroup I). All registrants met ICD-10 criteria for schizophrenia and schizoaffective disorder. Table 1 summarizes the statistical comparisons that were conducted between these three subgroups.
Selected psychosocial and clinical comparisons between a subgroup of registrants from the NISAD Schizophrenia Research Register and participants in the LPDS recruited through public MHS (with schizophrenia or schizoaffective disorder)
As shown in Table 1, relative to both of the LPDS subgroups, the Register sample was more likely to have: post-school qualifications, higher levels of face-to-face family support, higher premorbid social and work adjustment, lower levels of personal disability and higher overall social functioning. In addition, they differed significantly from the LPDS inpatient-recruited subgroup, having lower symptom levels for mania, reality distortion and disorganization, and lower social disability scores. There were no subgroup differences with respect to age, accommodation, pensions and welfare benefits, perceived availability of friends, substance use, current depression, and GP contact rates (by users) during the past year.
Overall, the symptomatology and disability means in Table 1 mirror the presumed chronicity profiles for the subgroups, with the community-recruited subgroup falling between the Register and inpatient-recruited subgroups. Depression and substance use, which are often comorbid with psychosis, were similar across the subgroups. It also seems likely that the Register sample was less disabled to begin with, having fewer premorbid adjustment problems, possibly contributing to higher rates of post-school qualifications and the maintenance of regular contacts with family members. Such features are also consistent with a later onset age for psychotic symptoms, however, this cannot be confirmed.
Finally, while the LPDS comparisons reported here provide a useful insight into registrants' characteristics and the representativeness of the database, they have their limitations. First, the demographic comparisons involved only a small set of characteristics, with the LPDS participants being recruited primarily from States outside the NSW/ACT catchment for the NISAD Register, and without the rural/regional representation observed in the Register sample. Second, the psychosocial and clinical comparisons were based on thefirst 50 registrants who completed the DIP, which covers only one-fifth of the current registrants.
Conclusions
We have documented the potential benefits and issues surrounding the establishment of large-scale collaborative research databases and provided a specific rationale for the development of the NISAD Schizophrenia Research Register.
The comparative analyses with the LPDS confirmed our belief that there are some self-selection factors associated with volunteering for the Register, generally indicative of lower current symptomatology and higher functioning. However, the psychosocial and clinical similarities with other samples are clearly more important, with the registrants meeting established diagnostic criteria for schizophrenia or schizoaffective disorder and reporting the high levels of lifetime disturbance that are typically associated with these conditions (e.g. relationship difficulties, substantial substance abuse histories, prolonged periods of unemployment and dependence on welfare benefits).
The Register provides a unique and invaluable educational and research resource in its own right, which should enhance opportunities across the spectrum of schizophrenia research. Importantly, the Register also provides a complementary recruitment source for researchers who tend to rely primarily on samples drawn from particular mental health services contexts. Additionally, because the Register's staff can access basic demographic and clinical information about registrants, as well as their patterns of recent research participation, they can provide valuable guidance and assistance during the subject recruitment phase. It may simply be the case that a particular gender and age mix is required, or the detailed research protocols employed in a particular project may necessitate the recruitment of individuals with higher levels of current functioning and/or premorbid intelligence (NART) scores within a particular range.
Now that the Register is firmly established, we need to ensure that it is appropriately maintained, nurtured and utilized, and that it realizes its potential to improve the overall quality and quantity of schizophrenia research in Australia.
Footnotes
Acknowledgements
The Schizophrenia Research Register is funded by the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD) and is hosted by the Centre for Mental Health Studies, University of Newcastle. The authors would like to thank the NISAD Clinical Measurement Panel for their support in the preparation of this paper: Philip Ward, Stanley Catts, Anthony Harris, Daren Draganic (and chaired by Vaughan Carr). We also thank all those people who gave so freely of their time to register with the database and participate in its activities.
The present report includes data collected in the framework of the collaborative Low Prevalence (psychotic) Disorders Study (LPDS), an epidemiological and clinical investigation which is part of the National Survey of Mental Health and Wellbeing, Australia 1997–1998. The team leaders in this study were: Assen Jablensky (Project Director, Perth, Western Australia), Mandy Evans (Canberra, Australian Capital Territory), Helen Herrman (Melbourne, Victoria) and John McGrath (Brisbane, Queensland). A complete list of investigators is available in Jablensky 
]. The study was funded by the Commonwealth Department of Health and Aged Care (Perth, Melbourne, Brisbane) and by local sources (Canberra). We acknowledge the mental health professionals who contributed to the LPDS and the many Australians with psychotic disorders who agree to participate.