The great challenge for exhaled breath analysis: embracing complexity, delivering simplicity

‘Life is not measured by the number of breaths we take, but by the ones we analyze’

As the headspace of the blood, our exhaled breath contains a vast array of substances and molecules that hold great promise for monitoring our health and for the diagnosis and management of various lung and systemic diseases [1]. With recent advances in technology, essentially anything in the blood that is potentially volatile or has a volatile metabolite can be measured in exhaled breath [2]. This includes substances we produce endogenously as part of our normal (or disease-related) metabolism whether this is local in the lung or systemic in origin [3–6]. Since we are constantly inhaling air from our environment as we breathe in the ambient air, exhaled breath can also reflect our environmental exposure(s) [7]. Furthermore, our breath contains volatile compounds produced by our ‘internal environment’: the bacteria in our gut and mouth [3]. Add to all of those volatile byproducts generated from our diet, medications, drugs, or toxins that we are exposed to and you get a very rich matrix that has great potential to revolutionize and personalize medicine [2, 3]. But in order to unlock the great potential of this highly complex resource, we need to find ways to understand its complexity and control or account for the sources of ambiguity.

Tackling such a monumental task requires transdisciplinary collaborations and partnerships among all the stakeholders and any and all other disciplines that can inform the field. This includes, but is not limited to, medical professionals (physicians, researchers, biologists, etc), scientists (chemists, physicists, biochemists, statisticians, etc), engineers, commercial and industrial partners, and regulatory agencies, among others. This critical need for a collaborative approach was the most important conclusion of the Breath Analysis Summit held at the Cleveland Clinic in 2007 [1]. The Summit focused on medical applications brought together industry executives and entrepreneurs with scientists and clinicians to discuss key trends, future directions, and upcoming technologies in breath analysis and medicine. It was very clear at the Summit that the major limitation in the breath analysis field at the time was not a lack of technology or the ability to measure biomarkers in the breath [2] but rather the fact that while scientist, physicians, and industry are all making progress in their own domains, there was very little meaningful and early interaction between these groups. Most interactions were afterthoughts rather than deliberately planned collaborations. Fortunately, not only did the Summit identify the critical need for a collaborative approach, but it also resulted in the forging of several such collaborations and attracted several new talents into the field.

One of several such successful outcomes was the establishment of collaboration between the Cleveland Clinic, NASA, OSU, and CWRU that attracted significant funding from the State of Ohio and established partnerships with several local, national and international institutions and industries all focused on the medical applications of exhaled breath analysis [8–10].

An additional measure of success for the Cleveland Breath Summit was the interest the Summit generated in breath analysis among other disciplines and societies like engineering. In this issue of Journal of Breath Research, we present selected papers from the first ever breath analysis meeting to be organized by Engineering Conferences International (ECI). This is a major milestone for breath analysis and for engineering. The meeting ‘Exhaled Breath Analysis Conference: From Sensors to Devices and Applications’, held in Barga, Italy, in 2010, brought together participants from across the spectrum of science, medicine and engineering in a week long conference that identified and discussed the recent advances and current challenges for breath analysis from all of these different perspectives. The compendium of publications in this issue will give the reader a glimpse of what occurred in that groundbreaking meeting.

Some of the recurring themes from prior meetings included the spectrum of breath analysis applications (medical, environmental, intelligence, etc), standardization of sample collection, the use of novel methods (to present, analyze, and report data), intellectual property issues (including funding and commercialization), and interaction with regulatory agencies. The exhaled nitric oxide story remains the main model to follow from discovery [11], to understanding of the biology [12–14], to standardization of methods [15, 16], to realizing the strengths [17, 18] and limitations [6], to approval by the regulatory agencies [19], to acceptance in clinical application and practice [20].

New themes also emerged including the importance of early and frequent communication among collaborators, the importance of getting early input from potential end-users (regarding needs and expectations), and the critical need to study and understand the biologic relevance of the compounds present in exhaled breath. This is relevant in the discovery phase (can help predict what compounds may be important and relevant to look for in the breath) but it is certainly crucial for the validation and application phase.

Finally, it was recognized that we need to understand the limitation of our own knowledge and to keep an open mind for new collaborations and new methods of measurement and analysis. For while we obviously know what we know (known knowns) and we may be aware of some of what we do not know (known unknowns), we need people from other disciplines to enlighten us about what they know that we do not (unknown knowns), and we will always be limited by what we do not even know that we do not know (unknown unknowns) (figure 1).

Figure 1.

Knowledge matrix. See text for explanation.

The only way for us to keep moving forward and meet the great challenges that face the breath analysis field today is to focus on what we know now and keep adding to the pool of knowledge by forging strong transdisciplinary collaborations with the many other relevant disciplines in the basic and applied sciences. This will help us handle the complex reality of our field and allow us to deliver the simple useful solutions expected by end users (figure 2) and thus fulfill the great potential and promise of breath analysis.

Figure 2.

Major challenge for breath analysis is to understand and handle complexity while delivering simplicity. A heat map of mass spectrometry data on the left will not likely be very helpful for end users (testing for a disease in the clinic for example). To be useful, this complex array of data needs to be simplified in a way that allows for decision making similar to the way traffic lights are used.

Yaron Bogin, Gaspard Pardon, Andras Bikov, Yoav Broza, Charlene Bayer, Noboru Suzuki, Anil Modak, Joachim Pleil*, Claudio Loccioni, Makoto Sawano, Koichiro Nagamine, Anton Amann*, Phillip Trefz, Andru Prescod, Elena Shnayder, Wolfram Miekisch, Simonetta Capone, Herman Bieber (ECI), Gagan Jodhani, Michael Epton*, Troy Hibbard, Gary Hunter*, David Grove, Bo Li, Ingrid Kohl, Jane Hill, Ann-Charotte Almstrand, Marco Righettoni, Malina Storer, Anna-Carin Olin, Sean Ellwood, Raed Dweik* (Chair), Jack Dummer, Terence Risby*, Sven Kelling, Trevor Smith, Kelly Paschke, Simona Cristescu, Jens Herbig, Stefano Ferretti, Tim Mottin, Jonathan Beauchamp, Petra Neff, Olavi Vaittinen, Joanne Shorter, Cristina Davis*, Michael Madden, Charles, Forbes, Dietmar Hein, Prabir Dutta*, Stephen Fowler, Julian King, Karl Unterkofler, Antoaneta Kazandzieva, Veronika Ruzsanyi (organizing committee*)