The Development of ISAAC
ISAAC started as a collaboration between mainly European and Australasian investigators but rapidly expanded during the mid-1990s to become a network covering all six inhabited continents (we have yet to recruit a regional co-ordinator for Antarctica!). This section charts the development of this worldwide consortium and ends with some reflections on the place of ISAAC in the world of the 21st century.
The globalisation of ISAAC(Neil Pearce)
Although ISAAC was started by research groups based in New Zealand, the United Kingdom and Germany, it was recognised from the start that it was important that the study be conducted on a truly global basis. The major contribution of epidemiology to the study of chronic diseases such as cancer and cardiovascular disease has arisen from studies at the population level, including analyses of patterns of disease prevalence and incidence across demographic groups, geographic areas and across time periods (“person, place and time”). For example, it was in the 1950s that it was first realised that colorectal cancer rates were high in Europe and low in Africa and this gave rise to hypotheses about the roles of fruit and vegetable intake and dietary fibre; similarly, it was realised that liver cancer rates were high in Asia, and this led to the discovery of hepatitis B as the major risk factor for liver cancer worldwide; more recently, international and regional comparisons in cervical cancer rates gave rise to the hypothesis that an infectious agent may play a role, eventually leading to the discovery of human papilloma virus (HPV) as the major risk factor for cervical cancer.
In contrast, prior to the ISAAC study, such standardised international comparisons had not been done for asthma - with the exception of the European Community Respiratory Health Survey, which had mainly been done in Europe. In fact, a huge amount of funding had already been spent on studying the “known” causes of asthma in affluent countries (e.g. air pollution, allergen exposure), but little was known about whether such risk factors were important globally. It was therefore decided, from the outset, to make ISAAC into a truly global study. This required that the study used simple inexpensive validated methods that could used anywhere in the world – a requirement which led to the splitting of the study into Phase I (which could be done anywhere) and Phase II (which would only be done in selected centres and countries). It also required that the ISAAC Steering Committee be truly global, and this was achieved by creating positions for Regional Coordinators.
The recruitment of Phase One regional co-ordinators(David Strachan)
At the time of the London Steering Committee meeting in December 1992, ISAAC officially consisted of only 4 centres from 2 countries. Just two years later, 107 centres from 42 countries had been recruited, and by the end of 1995, the Auckland Data Centre had received Phase One data from 110 centres. This remarkable expansion and successful completion of fieldwork relied critically upon the identification of able and willing regional co-ordinators around the globe. It was they who put the “I” into “ISAAC”!
The 1993 Steering Committee meeting was held in Geneva and followed by a meeting with representatives of the World Health organisation who had expressed an interest in ISAAC. This early interest from WHO led to the definition of ISAAC regions along the lines of WHO regions. However, in retrospect, it was not these official channels so much as personal contacts which led to the establishment of an effective network of regional co-ordinators (and, later, national co-ordinators) within ISAAC. In particular, during a period of sabbatical leave during 1993-4, Richard Beasley played a key role in promoting the concept of ISAAC outside of Europe and Australasia.
By the time of the 1994 Steering Committee meeting, the basic framework of ISAAC regional co-ordinators had been established, with attendance by:
Gabriel Anabwani (Africa: 4 countries, 4 centres participating in Phase One)
Bengt Björkstén (Northern & Eastern Europe: 5 countries, 5 centres)
Chris Lai (Asia-Pacific: 10 countries, 19 centres)
Fernando Martinez (North America: 2 countries, 3 centres)
Steve Montefort (Eastern Mediterranean: 5 countries, 6 centres).
The original ISAAC partners were represented by: Innes Asher (Oceania: 2 countries, 10 centres) and Ulrich Keil (Western Europe: 6 countries, 32 centres).
The following year, Javier Mallol (Latin America: 8 countries, 8 centres) was able to attend the Steering Committee meeting in Barcelona, and there was welcome news that Jayant Shah had recruited 21 Phase One centres in India. Jayant Shah was unable to attend the Steering Committee meeting in person until the October 2000 meeting in Auckland, by which time co-ordination of the African region had been split between Anglophone Africa (Joseph Odhiambo) and Francophone Africa (Nadia Aït-Khaled).
The network of regional co-ordinators remained remarkably constant throughout the last 15 years of ISAAC, and this organisational stability no doubt contributed to the smooth and successful implementation of Phase Three, both in the original Phase One centres and in new locations. In recognition of the expansion of ISAAC outside of Australia and New Zealand to Pacific island nations, Sunia Foliaki was appointed regional co-ordinator for Oceania, replacing Innes Asher, for Phase Three.
The globalisation of ISAAC Phase Two(David Strachan)
In contrast to Phase One, where globalisation was driven by the enthusiasm of regional co-ordinators, recruitment of Phase Two study centres followed a less structured approach. The original concept of Phase Two was to study in greater depth centres with diverse prevalences of asthma or allergy, as defined at Phase One, but this aim was never fully realised. Principally, this reflects the greater demands, both financially and logistically, involved in completing Phase Two fieldwork.
In the late 1990s, as the methods of Phase Two had been finalised, it appeared that it might become very largely a European study, and a small European Union Framework Programme 4 grant was awarded to create a “network of excellence” among the ISAAC centres in Europe. This later bore fruit in the form of a more substantive EU FP5 grant which supported the centralised analysis of data, serum IgE, dust and DNA from EU centres in Phase Two.
Phase Two fieldwork in many lower-income countries was supported by a partnership with another centre in a higher-income country. Examples include Albania, Ecuador and Ghana (partners with the UK), Estonia and Latvia (partners with Sweden), and centres on mainland China (partners with Hong Kong), These partnerships allowed some transfer of knowledge and expertise, and contributed to standardisation of methods across study centres.
In retrospect, the original plan to select Phase Two centres on purely scientific criteria based on the Phase One findings was perhaps too optimistic. As it turned out, there is considerable heterogeneity of asthma/allergy prevalence across the centres that were included and this has led to more informative between-centre analyses of symptom combinations and risk factor associations.
The incomplete overlap between the network of Phase Two centres and those involved in Phases One and Three has limited the extent to which the results from Phase Two can supplement and inform the Phase Three comparisons. Nevertheless, Phase Two has achieved its original aspiration to perform objective tests of asthma and allergy in diverse populations around the world.
ISAAC in the context of other European initiatives(Bert Brunekreef)
As with any good story, the ISAAC story must be one that’s rich, multifaceted and having all sorts of twists and turns. I’ll add a few of my own.
When ISAAC got started in the Bochum workshops, we had just completed a few fairly large respiratory symptom questionnaire studies among primary school children in the Netherlands. I say ‘we’ because there were two parallel activities, one based in the University of Wageningen where I was at the time focused on environmental determinants of respiratory disease in children – and one led by Bert Rijcken in Groningen, which was more focused on the use that school health services might have from respiratory symptom questionnaires in their daily practice. When we got invited to the second Bochum workshop, none of us could go but we sent a junior colleague, Bernard Groot, to find out what was going on at the time. We then decided we were unlikely to get funding for yet another series of symptom questionnaires, and that we better wait for an opportunity to join a phase two study if that was ever going to happen. Fairly soon after that, Bert (the other Bert….) made the brave decision to leave science to become an artist, and we in Wageningen became more and more involved in studies of outdoor air pollution.
I think it was in 1992 that I met a young German epidemiologist, Stephan Weiland, at the annual conference of the International Society of Environmental Epidemiology in Cuernavaca, and we got to talk about the interesting work that he had been doing on proximity to traffic and respiratory problems in kids. A few years later I was giving a speech on air pollution at our National Institute of Public Health and the Environment in which I briefly quoted one or two of those traffic studies. In the break, a man working for the province of South Holland came up to me and asked whether I was interested to do a study on proximity to freeways and respiratory health in children. Hs argument was that more and more homes and schools were being built near freeways (yes, it’s a small country, and space is precious….). We got some talented students involved in what was really a pilot study, but we did manage to include objective measures of air pollution exposure and respiratory health, and we found a fairly striking relationship between truck traffic density on the nearest freeway and lung function in the children we tested. That study stimulated our government to fund a much larger study on the topic, at a time when in Germany, the first ever ISAAC Phase two study had just gotten underway. I felt that the time was now right to try and jump on the ISAAC train and I contacted Erika von Mutius and Stephan to ask them whether they would be willing to let us use their protocols and apply those in our Dutch studies. Both were extremely helpful, and after a few visits to Muenster where Stephan and Ulrich Keil had moved at the time we were ready to launch our own ISAAC II study, focused on the role of traffic pollution in explaining variations in respiratory health among school kids.
Meanwhile, a concerted action had been launched in Europe led by David Strachan, and aimed at further cementing collaboration of ISAAC centers in Europe, including some work on serology and mite allergen determinations which we had going at the time. (For those of you not from the EU, the EU has a staggering variety of funding instruments, and ‘concerted actions’ are primarily meant to allow research groups to get together to discuss areas of mutual interest, without funding actual research). If my memory does not fail me too much, this action laid the ground work for a successful application for the ISAAC Phase II study which was coordinated by Stephan between 1999 and 2003 or so. We were privileged to be part of that effort with contributions from our own study population, and from our lab doing dust allergen and endotoxin analyses for all partners, and the harvesting from that seminal effort continues to this very day.
Then in 2003, Stephan asked me whether I would be willing to become part of the ISAAC steering committee, and I was truly honored to accept. It took me a while to actually get to the meetings but since 2005 I’ve missed only one, and they have been very enjoyable experiences indeed.
In 2006 and 2007, we were getting ready in Europe to propose a large scale study of the effects of long term exposure to air pollution on a variety of health outcomes, and Stephan was an enthusiastic and active member of the preparatory team to get this up and running. We met in early March 2007 in Barcelona to hammer out the last details of the proposal, and I will always remember with great sadness the day, just a few weeks later, that Gudrun Weinmayr called me in tears to tell me that Stephan had suddenly died. I couldn’t believe it. He was extremely fit, running marathons, and less than a year earlier I had accompanied him on a one hour plus jog at a meeting in (I believe) Salzburg which we both were attending. It just did not (and does not ) feel right that somebody so talented and vibrant would all of a sudden be taken away from us and (more importantly) from his wife and small children.
But then life, including ISAAC’s life, goes on. ISAAC made it to no less than 20 years, and to a great many achievements for science and society. I am extremely grateful to be part of it, and to have been able to make a few modest contributions.
January 2011, Auckland – Kuala Lumpur, Bert Brunekreef
ISAAC in the 21st century(Carsten Flohr)
We joined the ISAAC Steering Committee only a few years ago to complement its expertise, at a time when the study was already well under way. At its outset, the world of allergy and its needs was very different from what is required now. Even simple prevalence data was scant. There was also a lack of validated and standardised tools that could be used in large population-based surveys, and there certainly was no world map of the burden of allergic disease. All of this was already delivered in Phase One. In Phases Two and Three we have been able to look at individual risk factors of allergic disease (Phases Two and Three) as well as providing further prevalence data to look at trends (Phase Three). Part of this work is still underway.
Apart from its sheer size, the strength of the ISAAC data set is that it provides information on risk factors in developing countries, where allergic diseases have been only occasionally studied rare commodities until recently. As more and more populations adopt a western lifestyle in the 21st century, especially in urban centres of less affluent nations, ISAAC can make a contribution to the identification of key risk factors that drive allergic disease with the ultimate promise to aid disease prevention. For instance, we will seek to find the main environmental risk factors that explain the significant prevalence differences between ISAAC study centres. Another important area of interest is the impact of climate on allergic disease, and for this ISAAC prevalence data could be used in combination with satellite information. Furthermore, we need to study the lifestyle ingredients responsible for urban-rural prevalence and severity gradients as well as the influence of diet (mother and child), obesity, indoor and outdoor pollution. A lot more remains to be done!
I have been involved in the ISAAC work ever since Phase I started many years ago. It has been one of the most wonderful research endeavors that I have been involved through out my career. The achievements from the ISAAC work are clearly great examples of the results generated by collaborators who truly worked together for their common goals.
Behind this massive collaboration, one of the important driving forces to push things forward is the ISAAC Steering Committee. Members are from different parts of the world and each of them provides his or her unique expertise such that appropriate and important research questions are generated. More importantly, they would challenge each other regarding how these questions should be answered with what sort of methodologies and analyses.
I had the opportunities to join a couple of Steering Committee meetings as an observer such as the ones in Kenya and Tonga. I finally came face-to-face to the people with their names on many papers that I have read. In most instances, meetings are not my favourite activities, but the ISAAC steering committee meetings are different. There are honest exchanges of opinion and all members have one common goal in mind that is to ask the right questions to reveal the truth. From the genuine discussion during these meetings, one could feel the passion of each member for the work they were involved in. I was thrilled to have the opportunity to join this big family when I was invited to become one of the members in this Committee.
The ISAAC research network has provided answers to many of the questions that the research community has asked in the past 2 decades. Now, we have a lot more data with regards to the global variations and trends of asthma and allergies in childhood. What are the next important research questions in asthma and allergies? How can such large collaborative network help to answer some of these questions? These will be the biggest challenges for the ISAAC Steering Committee in the 21st century.
The global context of ISAAC in the 21st century
ISAAC has been the subject of positive editorial comment in the International Journal of Tuberculosis and Lung Disease, the leading voice of respiratory disease in developing countries, for its unique role in fostering research and critical thinking. They state ”ISAAC is a model that should be followed by all those of us who are committed to improving public health in low-income countries.” ISAAC uses a simple framework which enables standard measures and comparisons across geographic, cultural and linguistic boundaries which means it can be carried out relatively inexpensively, making it particularly suitable for use in developing countries and allowing “truly global participation”. This inclusive and encouraging approach has resulted in ISAAC becoming the largest study of its kind.
As stated by the Commission on Health Research for Development, “. . .for the world's most vulnerable people, the benefits of research offer a potential for change that has gone largely untapped”. Such research is essential to improve public health globally and equitably. A major barrier to achieving this is a lack of confidence of health care workers to involve themselves in research. ISAAC has addressed this obstacle and produced a body of knowledge that informs policy. The World Allergy organisation has reported that “studies such as ISAAC are a major step toward overcoming barriers to the worldwide diagnosis and treatment of asthma”.
ISAAC has established worldwide networks with organisations concerned with health in developing countries such as The International Union against Tuberculosis and Lung Disease (IUATLD) and the World Health Organisation (WHO). The ISAAC program is the only global study of paediatric asthma and allergy currently in existence and there is a clear and vital need for it to continue. ISAAC findings are cited by any organisation involved in monitoring and preventing CRD's and are used to inform global health initiatives which include WHO, and its NGO the Global Alliance against Chronic Respiratory Diseases (GARD). ISAAC publications are included in the “GARD Basket”, a package of information, offered to countries by WHO to assist policy decisions relating to CRD's.
1. Enarson D. Fostering a spirit of critical thinking: the ISAAC story. Int J Tuberc Lung Dis 2005;9:1.
2. Pawankar R, Baena-Cagnani CE, Bousquet J, et al. State of World Allergy Report 2008: Allergy and Chronic Respiratory Diseases. World Allergy Organisation Journal. 2008(Supplement 1):s4-s17.
3. World Health Organisation. Global Alliance against chronic respiratory diseases (GARD) basket: a package of information, surveillance tools and guidelines, to be offered as a service to countries. Geneva: World Health Organisation; 2008