Doing Well? Fulfilling the Promise of Precision Medicine a Paper by the Economist Intelligence Unit

Doing well? Fulfilling the promise of precision medicine A paper by The Economist Intelligence Unit

SPONSORED BY Doing well? Fulfilling the promise of precision medicine 2

Contents

3 Acknowledgements

5 Forward

6 Executive summary

10 Understanding precision medicine

27 Public health: The potential and limits of precision medicine

35 The challenges of integrating precision medicine into publicly funded health systems

48 Patient-centricity: The essential complement to precision medicine

59 Turning a vision into a reality

63 Endnotes

Acknowledgements

Doing well? Fulfilling the promise of precision Colleges of Nursing medicine is an Economist Intelligence Unit Daryl Pritchard, senior vice president, (The EIU) report that has been commissioned Personalised Medicine Coalition (PMC) by Qatar Foundation. The findings are David Taylor-Robinson, professor of public based on an extensive literature review and health and policy, University of Liverpool a comprehensive interview programme Don Brown, founder & CEO, LifeOmic conducted by The EIU between March and Gemma Bilkey, researcher, Department of September 2020. Health - Western Australia Genya Dana, head of healthcare The EIU bears sole responsibility for the transformation, World Economic Forum content of this report. The findings and views Geoffrey Ginsburg, director, Centre for expressed herein do not necessarily reflect Applied Genomics & Precision Medicine, Duke the views of the partners and experts. University The report was produced by a team of EIU James Morrow, general practitioner, NHS researchers, writers, editors and graphic Kawaldip Sehmi, CEO, International designers, including: Association of Patient Organisations Kelly Gebo, chief medical and scientific Katherine Stewart, Project director Officer, NIH All of Us Program Laura Blackburn, head of science, PHG Antonia Kerle, Project manager Foundation Antonella Bordone, Graphic designer Marc S. Williams, professor and director emeritus, Geisinger Genomic Medicine Emma Ruckley, Sub-editor Institute Matthew Bellgard, director of eResearch, Queensland University of Technology; Chair, Interviewees APEC Rare Disease Network Milan Radovich, associate professor of Our thanks are due to the following people for surgery, Indiana University School of Medicine their time and insights: Muin J Khoury, founding director, Office of Alan Balch, CEO, National Patient Advocate Genomics and Precision Public Health, US Association, US CDC Andrew Sinclair, co-lead, Australian Nahla M. Afifi, director, Qatar Foundation - Genomics Health Alliance Bio Bank Clara Gaff, executive director, Melbourne Nancy Kass, professor of bioethics and public Genomics Health Alliance health, Johns Hopkins University Colleen Leners, DNP, APRN, FAAN, FAANP, Philippa Brice, external affairs director, PHG director of policy, American Association of Foundation

Richard O’Kennedy, vice-president for research, Hamad Bin Khalifa University; vice-president for research, development and innovation at the Qatar Foundation Ronald Bayer, professor of sociomedical sciences, Mailman School of Public Health, Columbia University Said Ismail, director, Qatar Foundation - Qatar Genome Program Sally Davies, master of Trinity College, Cambridge, former Chief Medical Officer for England Sandro Galea, dean, Boston University School of Public Health Stefania Boccia, professor of hygiene and public Health, Università Cattolica del Sacro Cuore, Rome Takeya Adachi, research assistant professor, Kyoto Prefectural University of Medicine, Strategic Outlook toward 2030: Japan’s research for allergy and immunology Victor Dzau, president, US National Academy of Medicine Walid Qoronfleh, director of research and policy, Qatar Foundation - World Innovation Summit for Health

Forward

Qatar Foundation (QF) is a non-profit organization made up of more than 50 entities working in education, research, and community development.

Now in our 25th year, the mission of Qatar Foundation is to drive regional innovation and entrepreneurship, foster social development and a culture of lifelong learning, and prepare our brightest minds to tackle the biggest challenges facing our world today, and those that tomorrow will bring.

In everything we do, we strive to unlock the most precious resource of all—human potential. Education City, our flagship initiative, spans more than 12 square kilometers and hosts branch campuses of world-leading universities, a homegrown university, mainstream and specialized schools, and other research, scholastic, and community centers.

Together, these elements make Education City a unique model of academic and research excellence, pioneering a new approach to multidisciplinary, global education, and enabling breakthroughs that benefit Qatar and the rest of the world.

Aligning with our goal of catalyzing global conversations about the choices and challenges facing health policymakers around the world, Qatar Foundation is delighted to sponsor Doing well? Fulfilling the promise of precision medicine by the Economist Intelligence Unit.

Executive summary

Precision medicine1 is on the cusp of facilitating revolutionary improvements in how healthcare is delivered. This Economist Intelligence Unit white paper, sponsored by Qatar Foundation, looks at the promise of precision medicine, what it is currently delivering, and the challenges associated with its wider application in large health systems.

Key findings

Precision medicine is best understood as the possible outcome of four ongoing developments. Recognising that an agreed definition remains elusive, this paper conceptualises precision medicine as the This is expected to benefit all healthcare potential outcome of four interwoven, data- stakeholders: patients will have quicker related enablers: (1) the increasing volume access to the treatments they need, and will of data available to health systems; (2) vast be able to avoid the risks of taking incorrect growth in the kinds of data that are relevant medication; health systems will reduce waste to health systems; (3) the increasing ability to and improve outcomes; payers will receive store data in such a way that permits easier better value for money; and the overall health access to relevant information; and (4) the of populations will improve. quantum leaps in analytic technology that make it possible to draw greater insights from Current advances are limited but remain this information. highly promising. There are already a number of important examples of precision Hopes are high. This granular information medicine in action. Thanks to a better is expected to give us a much more detailed understanding of tumour genetics, more understanding of how an individual patient’s effective treatments are now possible for body works, what represents a health several cancers, notably those of the lung risk for that person, the peculiarities of a and breast. In the field of rare disease, given pathogen or tumour affecting that genomic sequencing is cutting diagnosis patient, and how any treatment might affect times for a large number of patients. both patient and disease. These insights Pharmacogenomics—the study of how a should allow medicine to move away from person’s genetics interact with particular its reliance on trial and error, enabling drugs—is a growing field, and genetic delivery of the right intervention (whether sequencing is being used to recognise curative or preventative) at the right time.

pathogen mutations. However, the impact of 2. ways that are misguided or harmful? precision medicine is limited beyond these efforts. To date, progress has largely been 3. Is precision medicine really something new, concentrated in genomic medicine, and or is it business as usual with slightly better this trend is expected to continue for the tools? foreseeable future. Careful consideration of these questions is necessary to prevent avoidable mistakes as Proof of value remains a pressing issue. Given the possible breadth of applications precision interventions are rolled out in any for precision medicine, it is challenging to health system. Despite the controversy, there determine whether the field as a whole is are some positive examples of precision tools cost-effective. Some interventions may be; being used for public health purposes. Two others may not. Data indicates that whole- of the leading COVID-19 vaccine candidates genome sequencing for rare disease diagnosis use messenger RNA, and detailed mapping and the sequencing of tuberculosis pathogens has been used to monitor and predict the to determine mutations are both worth the spread of diseases such as cholera, as well as cost. However, cost-effectiveness studies for risk factors for those diseases. In Yemen, this precision interventions are rare, and there is a mapping likely saved lives during the cholera lack of consensus on how to decide what level epidemic in 2017. of spending is worthwhile. Those seeking to incorporate precision The controversy around precision public medicine into healthcare systems will health highlights fundamental issues that need to address a diverse and complicated Innovation in healthcare must be resolved if precision medicine range of issues. systems is notoriously difficult. Integrating is to become more widely integrated precision medicine into standard care will into health systems. The concept of precision public health has caused significant require the creation of new care pathways and controversy in the public health field. This new kinds of interventions, all of which will controversy centres around three questions require different infrastructure. In most health that must be resolved before precision systems, this process is only in the initial medicine can be used widely throughout the stages. Those wishing to expedite the process healthcare sector: would benefit from considering the following issues. 1. How likely is it that precision approaches will add value, compared with standard practice Securing stakeholder commitments: today? Organisations that have made the greatest progress towards incorporating precision Does a precision approach change our medicine share the following characteristics: understanding of what public health means in strong leadership; payer buy-in, enabling

funding of the necessary investments; and Leading drug approval agencies are trying patient awareness and understanding of to find better ways to assess the safety and precision care, facilitating general acceptance. effectiveness of precision diagnostics and drugs, a growing number of which have Proving value: Advocates of precision been approved as a result of this effort. medicine in healthcare systems lack the However, no country has fully addressed the necessary data to demonstrate that it delivers challenges of using artificial intelligence within improved outcomes that justify the cost. New healthcare. health technology assessment procedures are needed that can consider the wider costs and To be successful, precision medicine benefits of precision interventions, as current must be delivered in a patient-centred approaches often cannot capture these way. Patient-centricity involves working with complexities. patients as co-creators of healthcare and health research, which involves a conversation Developing a workforce capable of of equals. Clinicians will need to help patients precision medicine: Even high-resource understand the implications of precision tests, healthcare systems lack the necessary the relevant data and the treatment choices. specialists to facilitate greater use of precision Both sides can then determine together medicine, notably geneticists, genetic what the patient values most in terms of the counsellors and data specialists. Non- outcome(s) of any intervention. Similarly, geneticist clinicians often lack confidence in health systems will need to conduct ongoing their knowledge of genomic interventions research in precision medicine in partnership (the cutting edge of precision medicine), and with patients to ensure that patient views on experts warn that medical curricula do not what data is relevant, and what issues should currently cover this field well enough. be studied, are taken into account.

Building the necessary infrastructure: Adopting patient-centricity can help Precision medicine relies on data, but to address some of the pressing ethical information within health systems is often issues surrounding precision medicine. fragmented and not readily useable. The nature of precision medicine, and Furthermore, laboratories often lack the particularly genomic medicine, raises several capacity to take on the substantial additional important ethical issues, including: testing required to expand precision medicine, even in wealthy countries. Data gathered for one genomic test may reveal information about a completely Creating an appropriate regulatory different condition, raising questions about framework for precision medicine: whether to inform patients and their families Precision medicine does not always fit of these “incidental findings”. This issue is easily into existing regulatory procedures. further complicated by the fact that an

individual’s germline DNA remains the same discussed in a patient-centred conversation throughout their life, which means that before a test is conducted, with the goal of incidental findings may not become apparent identifying what the individual would want to until years after the original test. be told in the event of such findings. Similarly, carefully explaining to patients the value of Data gathered from such tests would normally health databases, and working in partnership be added to databases to support future with them on research related to precision research. Patients can typically opt out of medicine, can help health systems to obtain this, but if many choose to do so, precision more and better information for the entire medicine will not advance. Even though the population. data is anonymised, there are no guarantees that future algorithms will not be capable of de-anonymising data. Indeed, for some kinds of test data, de-anonymisation is already possible.

Historically, most medical research has been conducted in populations where certain groups—often young males of European ancestry—are over-represented, compared with their share of the population. Relying on these databases might lead to unsafe recommendations for people from other groups.

Patient-centricity is an important part of any solution to these issues. For example, the possibility of incidental findings can be

Understanding precision medicine

Precision medicine has the potential to education to undergird the effectiveness of transform healthcare. By moving away this kind of healthcare. from trial and error towards more targeted, accurate diagnoses and treatments, people This paper looks at the promise and current should be able to live longer and healthier lives limitations of precision medicine, the barriers and social outcomes should improve, all with to its implementation in public health systems, less wasted time, money and energy. This is and the areas where policymakers – indeed, what medicine has always aspired to, but has all stakeholders – must focus their efforts in not yet been able to deliver. order to realise its potential.

While there is understandable excitement A transformation that defies precise about the promise of precision medicine, definition delivery will not be straightforward. There are several competing definitions of Innovation within health systems is precision medicine. The idea “might sound challenging at the best of times, and the simple, but it is not. If you ask people within nature of precision medicine means that the field, you will get different answers,” substantial process, training and infrastructure explains Dr Walid Qoronfleh, director of changes will be needed. These changes will healthcare research and policy at the World be challenging even in the most hospitable Innovation Summit for Health in Qatar. There environments. At the same time, all are also differences in terminology, with some stakeholders—including clinicians, patients, using the term precision medicine (particularly payers and the broader community—will need

in the United States)2 and others using the The power of data term personalised medicine. While there 7 have been attempts to distinguish between Data has always played a role in medicine, precision medicine and personalised medicine, and evaluating the potential medical a recent analysis described the differences as relevance of inherited characteristics is also “ambiguous”.3 established practice. Geoffrey Ginsburg, director of Duke University’s Center for One of the most commonly used definitions Applied Genomics and Precision Medicine, comes from the European Council, which explains that “often people believe that all the prefers the term personalised medicine and answers lurk in the genome, but family history describes it as follows: “A medical model using has been a tried and true way to look at risk characterisation of individuals’ phenotypes of disease since long before we had access to and genotypes (e.g. molecular profiling, people’s genomes.” Clinicians are also familiar medical imaging, lifestyle data) for tailoring with aggregating a range of data for insight. the right therapeutic strategy for the right The Framingham Risk Score, for example, first person at the right time, and/or to determine appeared in 1998 and is used to estimate the the predisposition to disease and/or to deliver ten-year probability of developing coronary timely and targeted prevention”.4 A commonly heart disease based on gender, age, blood used definition of precision medicine comes pressure, cholesterol levels and smoking from the US government’s 2015 Precision habits. Medicine Initiative, which describes it as “an emerging approach for disease treatment and The advances made possible by precision prevention that takes into account individual medicine lie in its capacity to enable medical variability in genes, environment, and lifestyle practitioners to access and evaluate more for each person”.5 specific and detailed information about their patients, and to then tailor interventions For the purposes of this paper, we use the accordingly. Even in modern medicine, the term precision medicine and conceptualise it clinician is constrained by the bounds of as the potential outcome of four interwoven, current medical knowledge. Clinicians often data-related enablers: (1) the increasing have to rely on generalities when diagnosing volume of data available to health systems; patients due to a lack of individualised data, (2) vast growth in the kinds of data that are placing a presenting patient into a general relevant to health systems; (3) the increasing category with others sharing the same ability to store data in such a way that permits apparent illness (which itself might be one of easier access to relevant information; and (4) several conditions at the molecular level). As the quantum leaps in analytic technology that a result, doctors often have to fall back on make it possible to draw greater insights from interventions that sometimes work but too this information.6 often do not.

James Morrow, a general practitioner and better social outcomes”. Colleen Leners, with the National Health Service (NHS) in DNP, APRN, FAAN, FAANP and director of Cambridgeshire in the United Kingdom, policy at the American Association of Colleges explains that medicine has traditionally of Nursing, agrees, explaining that precision taken a sort of “blunderbuss” approach, with medicine is “a radical shift in how each of trial-and-error applications of interventions. us can receive the best care possible based These interventions have often been shown on our unique makeup”. The capability to to work in only a small minority of the harness more and better information will be general population, which means that they central to this radical shift. Genya Dana, head sometimes result in “complete misses or of healthcare transformation at the World collateral damage”. Milan Radovich, associate Economic Forum (WEF), notes that “the way professor of surgery at Indiana University’s different people define precision medicine School of Medicine, describes this as “the is extremely variable, but there is collective tyranny of averages. All of medicine is based agreement that data is a pretty fundamental on averages.” Studies of pharmaceutical piece of the puzzle. Precision medicine is very effectiveness illustrate the problem: a 2015 much driven by data.” In the words of Donald Nature commentary reported that, in the Brown, the founder and CEO of LifeOmic United States, the top ten selling drugs helped (a health software company), “biology and only 4-25% of people taking them.8 This is the life sciences are becoming information better than nothing but leaves the majority of sciences.” those with such prescriptions no better off. “It is really important to be able to treat people Four data-related enablers will make precision more precisely,” Dr Morrow concludes. medicine possible, allowing for more fine- tuned risk assessments, diagnoses and Dr Qoronfleh describes precision medicine interventions: the volume of available data, as a new and holistic approach that will lead the nature of that data, the ways in which to “better care, better value, better health that data is stored, and the ways in which it is

analysed. Each of these enablers is discussed specific one to a molecular one, which has led in more detail below. to tremendous innovations”. There have also been advances in the speed of genetic testing, The volume of available data and the cost of this testing has fallen. With The first enabler is an increase in the Next-Generation Sequencing, laboratories quantity of information generated within can now sequence an individual’s entire DNA health systems. Although medical systems (Whole-Genome Sequencing) or only those have always collected data, the quantity of parts that produce proteins (Whole Exome collected data is increasing exponentially. Sequencing) within a day. In 2003 it cost According to Dell EMC, the pool of data around $50m to sequence the entire DNA of held by healthcare organisations worldwide a single human being; today it costs around increased by 878% between 2016 and $1,000 (and that price has stayed largely 11 2018.9 In the longer term, IDC, a market constant since 2015). intelligence firm, projects that the volume of While this genomic data holds great promise, information within the health sector will rise Victor Dzau, president of the US National at a cumulative annual growth rate of 36% Academy of Medicine, points out that between 2018 and 2025, well ahead of the “sequencing is only one of piece of information 10 global rate for all data (27%). Although not to drive the precision of prediction.” At the all data is relevant or useful, an increase in the molecular level, other kinds of data are likely quantity of available data means that there are to shed light on matters that are relevant to greater opportunities for clinicians to build a an individual’s health, including epigenomic more detailed picture of their patients’ health. data (the study of changes to heritable The nature of available data characteristics that do not involve DNA), proteomic data (the study of the collection This increase in the quantity of available of proteins in an individual), microbiomic information is driven in part by an expansion data (the study of all the bacteria, viruses, in the kind of data that is potentially relevant fungi and protozoa living in an individual) to health. For instance, increased knowledge and metabolomic data (the study of all small of the health implications of a single gene molecules within an organism). Alone or in (genetics) or a combination of genes combination, these factors could conceivably (genomics) within individuals, pathogens affect susceptibility or immunity to disease, and tumours has reshaped medicine, with reactions to medication and even quality of important results. Dr Marc Williams, director life. emeritus of the Geisinger Genomic Medicine Institute, notes that our “understanding of Information on lifestyle is also likely to be cancer is going from an organ and tissue- essential to understanding various aspects of

data, information from wearables and In our DNA survey responses from 1m people. It has a Cost of sequencing a single whole human particular focus on previously understudied genome (in USD) groups within the population, such as ethnic minorities, women and older individuals. Since 100mn enrolment began in 2018, the programme

10mn has reached about a quarter of its hoped-for participants. 1mn The UK project is focused on collecting whole

100,000 genomes from patients with cancer and rare diseases, and from the family members of 10,000 patients with rare diseases. It was able to reach its goal of 100,000 participants in 2018, 1000 six years after it took its first sample. China, Estonia, Saudi Arabia and Turkey are also 100 aiming to collect repositories of genomic data 2001 2005 2010 2015 2020 on 100,000 people. Other countries have projects of differing sizes.13 Qatar, for example, Source: National Human Genome Research Institute plans to eventually collect information and other molecular data from all of its residents, a person’s health. Many individuals are already which will be matched with medical records. collecting this data themselves, and are happy Richard O’Kennedy, vice-president for to share it. According to a 2019 Pew survey, research at Hamad Bin Khalifa University and 21% of US adults have a fitness tracker or vice-president for research, development and smart watch, and of these, 53% think it is innovation at the Qatar Foundation, reports acceptable for the makers of fitness apps to that they are initially concentrating on Qatar’s share their data with researchers looking into permanent population and have already the link between exercise and heart disease.12 collected around 20,000 samples. The growing volume and breadth of Dr Kelly Gebo, former chief medical and information that is relevant to health is scientific officer for the All of Us programme, prompting governments around the world to current professor of medicine at the Johns create large databases of medical data, such Hopkins University School of Medicine and as the All of Us programme in the United practising physician, explains that rather than States and the 100,000 Genome Project in the being national versions of the same exercise, United Kingdom. The All of Us programme “each [of these programmes] is slightly casts a wide net, seeking to combine DNA different in their objectives.” In the United samples, electronic health record (EHR)

States, for example, the focus is on creating remains a work in progress (as discussed a large database that will help researchers later in this paper). However, in the long learn how biology, lifestyle and environment term, the ability to store and access large affect health. In the United Kingdom, the amounts of data is likely to be more important aim is to gain genomic-related insights into to precision medicine than the database specific conditions, while in Qatar the goal projects that governments are currently is to integrate genomic data with healthcare undertaking. This is acknowledged in France’s records for direct use in clinical contexts. Dr Genomic Medicine Plan 2025, which aims Gebo adds that the people working on these to develop national capacity to sequence different programmes share expertise and 235,000 genomes per year.17 This goal may best practices, as each initiative ultimately be superseded by technological progress, seeks to leverage better, more detailed health as the Global Alliance for Genomics and data to improve medical outcomes. Health estimates that 60m people will have their genomes sequenced annually as part of Data storage regular healthcare by 2025.18 As Dr Brown explains, “most health information systems were not designed for this era of precision medicine. Data has been Running along tucked away in hard-to-use repositories.” Projected number of whole genome sequences However, there have been advances in run per year for cancer and rare disease how to store the growing array of available Rare disease Cancer Combined health data, with an emphasis on ensuring accessibility and usefulness. One important 350 advance is the widespread adoption of EHRs. 300 According to a 2018 survey, 96% of general practitioners in the European Union had 250 some sort of EHR for their patients;14 the most recent equivalent figure for the United 200 15 States is 86%, based on 2017 data. EHRs 150 were originally intended to help integrate care and improve administration, but researchers 100 have started to demonstrate that, with the 50 correct safeguards in place, aggregated EHR data can inform large-scale studies, especially 0 when specialised disease registries may not be 2018 2020 2022 20242 026 2028 2030 available.16 Source: Ewan Birney et al. 2017 Finding ways to store and share information

These numbers will soon far surpass the current largest databases of molecular data. It has happened before. In Nature in 2012 an international research consortium published the results of an effort to provide the most detailed map of the diversity of human DNA. It contained just over 1,000 genomes.19

Data analysis

The final data-related enabler of precision medicine is rapid improvement in data analytics, particularly artificial intelligence (AI). Without this, much of the rest would be of limited use. As Dr Williams explains, “human cognitive capacity is not increasing. With precision medicine, you are dealing with very much in the early stages, making it way more variables. You are going to have to challenging to discuss what medical AI use assistance from computer systems.” With will look like in practice. While there are a this technological assistance, clinicians are number of pilot projects, a Nature Heredity expected to gain access to extensive insights review this year found “few examples of Big that were previously hidden in healthcare Data being leveraged in healthcare despite data. Indeed, Dr Qoronfleh believes that the opportunities it presents for creating “as healthcare becomes more digital, it will personalised and effective treatments”.20 A decode biology. This is the future of medicine.” 2020 report by the University of Cambridge and the PHG Foundation, a health policy think Technology will play two key roles in precision tank, explained that while “AI is contributing medicine: finding links between the attributes important incremental improvements of patients with health risks, diseases, and in clinical genomics analysis including the outcomes of prevention or treatment phenotyping in rare diseases and cancer, and interventions; and alerting clinicians to the variant analysis and interpretation,” the “vast health implications of specific information majority of AI activity in genomics is within the learned about one of their patients. Just as research phase”.21 a blood test outside of normal parameters is flagged for the ordering clinician, EHR The case for precision medicine software could signal a potentially problematic Improvements in data collection, storage combination of health data. and analysis will help to facilitate the use of The application of AI in medicine remains precision medicine, but what are the benefits

of this approach? With precision medicine to more accurate, evidence-based expected to improve healthcare in a number information, precision medicine will give of different ways, we discuss possible gains medical practitioners a better sense of the at the patient, health system and population effectiveness of their interventions, as well as health level. the return on investment for care pathways and protocols. “You can make better decisions Patient-level gains which leads to better patient outcomes,” Precision medicine is expected to provide he explains, “because you are shaping patients with more accurate and detailed your strategy based on information and individual diagnoses, enabling the selection knowledge”. of the most effective treatment for the given Population health gains set of circumstances. Dr Morrow adds that eliminating inappropriate options will be just The role of precision medicine in public health as important: “Precision is as much about remains a matter for debate (discussed in protecting patients from adverse effects of more detail later in this paper). However, therapies as targeting beneficial ones. We it is possible that precision medicine will need to avoid doing harm to people.” have important benefits at the population health level if it is incorporated into national Earlier diagnoses are also likely. As Dr Brown policy and health strategy. While promising, explains, “Alzheimer’s, Parkinson’s, cancer— the extent to which these gains can be precision medicine could allow us to spot delivered for patients, healthcare systems these much earlier. The earlier you can spot a and population health will depend on how problem, the more quickly you can deal with precision medicine is translated from theory it.” This may mean that diagnoses start to into practice. overlap with recognition of heightened risk, a benefit that polygenic risk scores may soon Current progress: Promising but still exploit (discussed later in this paper). Indeed, limited one of the great hopes is that prevention could become increasingly personalised, enabling Precision medicine has the potential to people to understand how their own DNA and radically shift the practice of medicine. Dr other molecular attributes may affect their Dzau notes that discussions about precision individual health risk profiles. medicine tend to involve “a complex mix of science, aspiration and hype”. In practice, the Health system gains gains have been less than revolutionary so far.

At the health system level, Dr Qoronfleh Nobody is downplaying some important points out that by providing access advances. However, as Dr. Leners explains,

“precision medicine is not an unattainable treatment,24 but in 2018 and 2019 the US Food futuristic goal. It is already happening in and Drug Administration (FDA) approved 103 certain situations,” where important advances new molecular entities, 36 of which could have been made. According to Dr Williams, be described as personalised medicines. the areas that are “furthest ahead” are Of these, 14 are for some form of cancer.25 oncology and rare disease, with some more However, advanced health systems are not limited progress in pharmacogenomics and necessarily adopting these innovations at pathogen identification. scale. A recent study from Germany found that, of those patients diagnosed with the kind Oncology of lung cancer for which new treatments might Within oncology, non-small-cell lung cancer work, only 27% were tested for the relevant 26 and breast cancer have seen the biggest biomarkers. advances, although biomarker testing has Rare disease been integrated into standard care for neoplasms at some other sites too, including There has also been rapid progress in rare melanoma, chronic myeloid leukaemia and disease—a term that refers to between gastric cancer.22 Lung cancer, in particular, 6,000 and 7,000 conditions that affect very shows what personalised medicine can do: few people. Although the precise threshold survival rates (while still low) have increased for being defined as a rare disease varies by four to five times for those diagnosed as country, the European Union’s definition (one late as stage IV, if EGFR or PD-L1 mutations case per 2,000 people) is the most commonly indicate that certain specific medicines may used. Most rare diseases appear far less be effective.23 frequently in the population, with around 85% of known rare diseases affecting one Much of this progress has been recent. In person per 1m population. However, the sheer late 2018 just 11 genetic mutations within number of these diseases means that about any neoplasm indicated use of a specific 6% of the global population has at least one

such condition.27

The vast majority of rare diseases are genetic conditions, which has allowed precision medicine—and in particular, genomic medicine—to transform the field. The impact is not so much on treatment, although there has been progress there. Fifteen new molecular entities approved by the US FDA in the last two years have been for treatment of a rare disease.28 The greatest impact has been seen in the area of diagnosis, a process that typically takes many years of frustration for patients with rare diseases (see the box on a precision shortcut for the diagnostic odyssey).

A precision shortcut for the diagnostic odyssey: Precision medicine revolutionises care for patients with rare diseases

Matthew Bellgard, director of eResearch at programmes illustrate what this looks like at the Queensland University of Technology scale: the Undiagnosed Disease Programme (QUT) and chair of the Asia-Pacific in Western Australia (UDP-WA) and Economic Cooperation (APEC) Rare Disease Japan’s Initiative on Rare and Undiagnosed Network, notes that “rare diseases rapidly Diseases (IRUD). These programmes expose gaps in large health systems and demonstrate the importance of embedding highlight the need for a close alignment new sequencing technology within expert between precision public health and medical care and using data analytics to precision medicine.” The issue is not simply understand test results. a lack of treatment options; with over 6,000 identified rare conditions (defined as The Undiagnosed Disease Programme affecting fewer than one in 2,000 people) The UDP-WA brings together a team of and with more such diseases found every experts in different rare diseases at a single year, obtaining a correct diagnosis can be a location, so that patients have one-stop struggle in itself. access to care. The programme accepts A commonly cited US study reports that, on patients with complex multi-system average, the typical patient consults over conditions who have generally had multiple seven doctors and waits 4.8 years between specialist consultations and hospital symptom onset and accurate diagnosis.29 admissions. Once a patient has enrolled In Australia, a similar study found that the in the programme and seen a genetic typical patient consulted five physicians, counsellor, an expert panel of specialists and that the journey to accurate diagnosis reviews the case. For a limited number of took 4.7 years. For 10% of patients in patients, the panel is able to reach a correct Australia, the process took more than diagnosis based on existing information and 20 years.30 This frustrating “diagnostic test results. If this is not the case, the panel odyssey” can involve numerous referrals recommends a series of diagnostic tests. between experts in different parts of the These normally include both whole-exome health system; any number of tests; and at and whole-genome sequencing. least a few incorrect diagnoses, leading to The panel reviews the test results and, with treatments that prove ineffective. the permission of the patient (and where However, the large number of rare diseases relevant, the parents), shares them with arising from genetic mutations raises the national and international partners. This possibility of using genomic tests to speed provides access to, and builds the volume up the diagnostic odyssey. Two Asia-Pacific of, the body of international shared data on rare diseases, increasing the possibility

of finding a diagnosis for the individual in question. Contributing the patient’s data also supports future diagnoses for other people.

The patient then receives a full report. If a diagnosis is found, the case is referred to the health system for appropriate care where available. If there is no diagnosis, the patient is told of any new findings and given suggestions for further tests. In both situations, the individual living with the rare disease is also referred to relevant support groups or patient communities.

This combination of measures is not perfect, as it only diagnoses around Initially, a committee compares existing test half of the patients who take part in results and clinical data with the country’s the programme. However, this is still a national rare disease database, in the hope significant achievement, given that many that this facilitates rapid diagnosis of any of these patients had not been previously known condition. Should no diagnosis be diagnosed.31 forthcoming, the team can send biological samples from the patient and family Initiative on Rare and Undiagnosed members to one of five analysis centres for Diseases genetic sequencing or any other potentially valuable test. The results are returned to the Japan’s IRUD, which began in 2015, Clinical Centre and recorded in the national shows how a programme similar to the database. If this leads to a diagnosis, the UDP-WA can be scaled up. (Japan’s information is communicated back to the population is over 120m, compared with referring primary care clinic, which provides 2.6m in Western Australia.) Anyone in appropriate treatment and counselling.32 the Japanese primary care system who appears to have a genetic condition but By mid-2018 the IRUD had made more than remains undiagnosed for more than six 1,000 diagnoses (around 37% of patients months can be referred to one of over 400 who went through the programme) and IRUD partner hospitals. These are linked identified 18 new diseases.33 Although a with around 40 Clinical Centres, where higher rate of diagnosis is always the goal, multi-disciplinary diagnosis committees the estimated number of undiagnosed review cases. rare diseases in Japan is just over 37,000,34

which means that the IRUD has made a significant contribution. The project’s next phase, IRUD Beyond, will increase international data-sharing on rare disease and use genetic insights from the diagnosis of conditions to inform research on potential treatments.

Both the UDP-WA and the IRUD are available through public healthcare systems. Although a number of countries have similar programmes, including the United States, South Korea and Canada, their wider expansion will depend on whether they provide value. Clara Gaff, executive director of the Melbourne US$5,900. (This included the higher cost Genomics Health Alliance, explains that of reproductive services, because parents there is “concern from governments that of the diagnosed children were much more precision medicine will markedly increase likely to feel sufficiently reassured by the healthcare costs.” news to have another baby.)35

The data should reassure policymakers. Takeya Adachi, former programme officer While cost-effectiveness studies do at the IRUD, reports that perhaps the not exist for the IRUD and the UDP- best evidence of success is the impact on WA, Dr Gaff’s organisation has tracked healthcare beyond the field of rare disease. relevant information for the nearly 4,000 Dr Adachi is now taking a leading role in patients it treated between 2015 and Strategy 2030, Japan’s ground-breaking 2019. It found that, in general, “genetic new strategy for allergies and immunology, testing can provide more answers, at which seeks to use precision medicine lower cost per diagnosis, than a standard to target small populations with similar investigation.” Substantial savings also mechanisms to address their conditions.36 come from having to conduct fewer tests, Dr Adachi notes that the “IRUD was as well as the ability to begin treatment mentioned in the strategy document as more quickly. Dr Gaff and her colleagues an example of good practice. Even outside recently published research that showed of the fields of oncology and rare disease, that for 80 ill infants tested, the average many researchers, companies and patients cost per quality-adjusted life year (QALY) are realising its importance and success.” gained from the intervention was around

Pharmacogenomics The near future is still genomic

Pharmacogenomics—which uses genomic These early applications of precision medicine data to indicate how a given drug will affect an in the fields of oncology and rare disease are individual—is another promising avenue for no accident; they reflect both the extent of precision care. Roughly 20 genes have been medical need and the current limits of science. identified as having a clinically relevant impact Dr Adachi explains that these two pioneering on over 80 medications, in fields including fields have three common characteristics: cardiovascular disease, mental health and the severity of the conditions, many of cancer. Taking this information into account which are fatal; the frequent lack of effective can have a substantial impact on patient care. treatments; and the availability of genomic In one study of patients with depression, sequencing. “This is not necessarily performed doctors checked genomic data before in precision medicine,” he explains, but in choosing recommended medications. This led both oncology and rare disease “you can to greater patient adherence a year later, as easily imagine how to use it.” The same can well as cost savings of over $1,000 per person be said for pharmacogenomics and pathogen per year. 37 Dr Gebo reports that clinicians in identification. the United States are increasingly checking for these genetic markers before prescribing. Despite the breadth of possible data that Various pilot projects for using this testing in may be useful for precision medicine, in the community have taken place, largely in current practice the field largely relies on North America and Australia, but the practice genomic information. A recent academic has not yet become widespread.38 review of projects that describe themselves as precision medicine found that 84% only Pathogen identification collected biospecimens—something done predominantly in genetic research. Of the rest, Genomics could also be used to identify 42% combined biospecimens with EHRs.40 pathogens more precisely. NHS England, for Andrew Sinclair, co-lead of the Australian example, is using Whole-Genome Sequencing Genomics Health Alliance, explains that while to test bacteria in all new cases of tuberculosis “genomics has impacted everything, the other 39 in order to determine drug resistance. ‘-omics’ haven’t quite caught up.” Dr Williams Dame Sally Davies, master of Trinity College, agrees, noting that “things like the microbiome Cambridge, and former chief medical officer and proteome are ultimately going to be really for England, reports that this practice has important, but there is no evidence for added reduced the testing turnaround time by six value [currently], only additional cost.” weeks, allowing more rapid prescription of the most effective medication for each case. The integration of data beyond the genomic

into precision medicine is unlikely to be rapid. the full promise of this new approach will be Dr Williams explains that our understanding achieved, particularly given the long record of of these other areas is less advanced than incorrect predictions in the field. genetics, which means that “a lot of discovery still needs to take place.” As this occurs, As a result of this uncertainty, expectations however, it will become more difficult to find about how precision medicine will expand in patterns, because while DNA (at least germline the near future tend to reflect new uses of DNA) remains fixed throughout an individual’s genomic information. The field of cardiology life, data on one’s microbiome and lifestyle can is predicted to see advances because, as Dr change rapidly. This data is also more costly to Williams explains, it “has a high burden of obtain on a routine basis. Dame Sally Davies disease with single gene origins which affect believes that pulling clinically valuable insights a substantial number of folk”. Progress is also out of such data “will be difficult. It will need likely in the genetic screening of neonates. machine learning to bring it all together, but in Indeed, Qatar already performs such general it is not around the corner.” screening for 28 disorders. Dame Sally Davies also expects increased use of polygenic risk This does not mean that the ultimate goal of scores to stratify populations in large-scale multi-data precision medicine is untenable. screening programmes and provide better Dr Dzau reports that “most of us would agree clinical management. Pilots of polygenic that science will eventually get us there.” He screening are already being conducted notes that recent advances in science and for breast cancer surveillance, although medicine—such as the rapid development substantial work remains to be done.41 Dame of COVID-19 vaccine candidates, driven by Sally Davies adds that another promising advances in genetic sequencing and vaccine avenue is the “fast, effective diagnosis of technology platforms—would previously pathogens”, which can now occur in a matter have been unthinkable. However, he adds of hours rather than days. that he is unable to pin down “how soon” It is also likely that genomics will play some

role in prevention. Dr Williams reports that be available, rather than what technology Geisinger Health in the United States had is currently able to deliver. Evaluating cost- conducted exome sequencing of nearly effectiveness is also challenging because 145,000 of its patients by 2020 through precision medicine will work very well in its MyCode programme, notifying care some cases but is unlikely to be practical in providers if one of roughly 60 reportable others. The same is true for other medical genes is found.42 Since then, two major Boston approaches. For example, while surgery is hospitals have opened preventative genomics cost-effective for acute appendicitis, almost clinics: Brigham and Women’s Hospital and certainly it is less appropriate for a mild Mass General. headache.

As these advances demonstrate, precision So far, the evidence showing the cost- medicine is far from just hype; new tools— effectiveness of precision medicine is mixed. some of which are life-saving—have already Certainly, some interventions in general, and appeared and will continue to emerge. on specific populations, have a good evidence Nevertheless, it is still far short of what its base (see the box on rare diseases). However, advocates promise it will deliver. For now, Dame Sally Davies notes that while good precision medicine’s biggest impact is likely to cost-effectiveness evidence is available for involve wider clinical applications of genomic “some mutations and treatment, I don’t think medicine that address a range of previously it really exists beyond limited scenarios”. unmet challenges. Using a range of integrated Laura Blackburn, head of science at the data to build a highly detailed picture of PHG Foundation, agrees: “Saying precision individual health remains some way off. medicine saves money is a comment that gets thrown around, but I have not seen much Is precision medicine worth it? evidence.”

Will precision medicine deliver better care A global review of cost-effectiveness articles than the current standard, and in an affordable on precision medicine interventions that way? In other words, is it cost-effective? have been published in academic journals Unfortunately, the answer to this critical also paints an ambiguous picture. Of the question remains unclear. Certainly, the publications included in the review, 28% were potential for savings in health systems is huge. either inconclusive or found the intervention A 2015 article in The Lancet projected that not to be cost-effective. The point at which if personalised prevention could reduce the a given intervention was deemed cost- incidence of heart disease in the United States effective also varied markedly. In some US by just 10%, this alone could save $114bn studies, an intervention that cost less than 43 over the ensuing five decades. However, $200,000 per QALY gained was considered such projections illustrate gains that might

cost-effective, which is more than five times more expensive than the standard threshold used by the UK’s National Institute for Health and Care Excellence. The review concluded that “Due to the many factors which influence cost-effectiveness and the varied thresholds of willingness-to-pay applied, the cost- effectiveness of [precision medicine] remains unclear.” 44

Dr Ginsburg notes that while the value proposition for precision medicine for payers remains “ill-defined”, it is only one part of the puzzle: “We are in the early stages of building the value models for patients, providers, health systems and countries. We need to look through all these different lenses because various stakeholders may have different views on value.”

Public health: The potential and limits of precision medicine

Another terminological muddle prevention, infectious disease control, environmental protection and sanitation, Some of the most intense discussion regarding disaster and health emergency preparedness the wider applications of precision medicine and response, and occupational health, among has occurred in the field of public health. others.”45 While public health does not exclude This has highlighted a number of issues that activities at the individual level, its main focus are likely to require careful consideration as is on the population as a whole or defined sub- precision medicine moves beyond (relatively) populations. straightforward genomic conditions to address more multi-factorial challenges. Defining precision public health is more challenging. “Most thoughtful people in this It is useful to begin by defining public health. space recognise that the definition of precision According to the World Health Organization public health is not so clear,” explains Sandro (WHO), public health encompasses any Galea, dean of the Boston University School “organised effort by society, primarily of Public Health. One particular point of through its public institutions, to improve, contention is the nature of the link between promote, protect and restore the health of precision medicine and precision public the population through collective action. It health. This was evident in a 2018 edition of includes services such as health situation Frontiers in Public Health that focused on analysis, health surveillance, health promotion, precision public health, in which one article

contended that “precision medicine and What might this look like in practice? precision public health are independent” while another argued that precision public health In public health, the tools, technologies “sits at the nexus of precision medicine and and approaches of precision medicine have public health”.46 Further complicating matters, been implemented in specific areas, rather Dr Gemma Bilkey, from the Department than across the entire field. Progress has of Health in Western Australia, explains been slower than in the field of medicine, that “people sometimes use the two terms with much of the literature still discussing interchangeably, but they represent different possibilities rather than concrete projects. (though complementary) entities.” Nevertheless, precision public health interventions are starting to appear. Muin Khoury, founding director of the US Centers for Disease Control and Prevention’s Research has been conducted to explore (CDC) Office of Genomics and Precision Public how advances in genomics could be applied Health, believes that “criticism [of the very to a number of public health tasks, notably idea of precision public health] may arise from screening and infectious disease surveillance. differing understandings of what constitutes As discussed earlier, research is investigating precision public health.” Dr Khoury describes how to use polygenic risk scores for certain precision public health as “next-generation cancers in screening programmes, and public health.” It is, he says, about asking sequencing is being used at the health system “how the emerging abundance of data and its level to identify drug resistance in tuberculosis associated predictive analytics can contribute in the United Kingdom. Smaller programmes ... by including more extensive information in have also used genomic sequencing to identify public health assessment of disease burden, outbreak sources and track transmission of facilitators and barriers to evidence-based MRSA, Ebola, HIV, Yellow Fever and the Zika 47 intervention implementation and outcome virus. Most recently, precision medicine tools measures, as related to person, place and have been used in various ways in response to time.” He adds that this data is not exclusively the COVID-19 pandemic. genomic and could include “biomedical, socio- demographic, environmental, geographic and other information”.

For the purposes of this paper, we conceptualise precision public health as the application of the tools, technologies and approaches of precision medicine to the long- standing tasks of public health, where doing so might prove useful to public health goals.

Precision public health’s contribution to the fight against COVID-19

The COVID-19 pandemic is the dominant the speed of vaccine development beyond healthcare issue of 2020. Responsibility for anything possible in the past.49 responding to the pandemic falls squarely in the field of public health, and precision tools Pathogen genetics have also played a are playing a key role. significant role in disease surveillance in two important ways. First, they have been used Work involving the genomics of the to monitor whether the virus is mutating pathogen is playing a dominant role in in a manner that might vary its severity precision public health responses to or vulnerability to vaccines or treatment. COVID-19. The US CDC’s web-based Public Through this work, researchers have found Health Genomics and Precision Health that COVID-19’s DNA is slowly changing. Knowledge database maintains a dedicated For example, the D614G mutation—so Coronavirus Disease Portal of relevant called because of a change in the amino published scientific literature, online news acid at position 614 in the virus’s spike and reports. This portal already has over protein—has gone from being relatively rare 7,400 entries. As of 8 September 2020, it to nearly universal in samples of the virus. characterised 68% of the site’s content as It remains unclear if (and how) this change genomic, defined as “the use of pathogen will affect pathogen severity, prevention or and human genomics and advanced treatment.50 This genetic monitoring should molecular detection methods in discovery, warn public health officials about potential clinical and public health investigations changes in the virus well before they involving COVID-19”. 48 become apparent in affected people.

The highest profile genomic public health Second, genetic variations in the virus activities involve the search for a vaccine. have allowed better surveillance of how Two of the leading candidates, Moderna’s the disease is spreading. In the early stages mRNA-1273 and Pfizer’s BNT162b2, use of the pandemic in the Netherlands, mRNA technology—a novel approach that analysts used whole-genome sequence has never led to a human vaccine before. analyses and other epidemiological The vaccine implants RNA into recipients’ techniques to understand and estimate cells, causing the affected cells to make transmission within the community. This specific elements of the virus but not the gave policymakers better information whole pathogen. The person’s immune as they contemplated workplace and system then learns to attack these as school closures.51 At a more global level, foreign intrusions, in theory priming it to Nextstrain, a project of the Fred Hutchinson respond quickly if infected by the whole Cancer Research Center in Seattle, is virus. This approach has helped to increase using minor mutations in samples of virus

DNA to track how the disease has spread in susceptibility because of attributes worldwide. Although the project has not in host DNA.56 Alternatively, it may be published examples of policymakers using related to depressed social determinants, such data, its daily updates make it a viable as hypothesized by Dr Khoury, founding tool. Analysis of the results can also help director of the US CDC’s Office of officials understand what works (and what Genomics and Precision Public Health. does not) when considering responses such If that is the case, he explains, “Precision as travel restrictions.52 public health represents a tool that could be developed by using more localised Important precision public health research analytics, to help assess the differential is also taking place without any genomic risk and burden of disease and death element. For example, in the early stages suffered by sub-populations such as ethnic of the pandemic, before rapid testing was minorities and rural communities. It could available, AI was applied to CT scans for then gear and tailor the decision-making 53 case identification purposes. Other uses and policy responses that will be needed as arose as this became less necessary. In we move forward.” some instances, the precision intervention has involved analysing a range of The higher death rate could also be due information simultaneously. In Atlanta, for to a combination of social and physical example, the mayor decided to roll back causes. A recent (not yet peer-reviewed) the city’s reopening (after lockdown) after UK study published in MedRxiv found that, seeing the joint effect of the number of among other causes, lower socio-economic new infections, the percentage of positive status and non-European ancestry both infection test results and the availability of increased COVID-19 susceptibility and hospital beds.54 severity, but in a statistically independent way.57 Only through precision analytics can Precision analysis may also help to explain we understand what explains these race- why certain people, or people in specific based differences in the current pandemic, locations, appear to be more susceptible to and therefore how to prevent unnecessary severe cases of the disease. For example, deaths in some groups in the future. two recent studies—one from Italy, the other from India—indicate that higher levels These are just a few examples of how of air pollution increase the chances of precision medicine tools and technologies getting the disease and of dying from it.55 are being used in the fight against COVID-19, highlighting both the current role Data analytics may help to explain one of and potential future role of precision public the most worrying trends of the pandemic: health in enabling more effective pandemic the higher death rate among ethnic responses. minorities in various countries. Research is underway to investigate whether this disparity may reflect a difference

Academic research that applies data analytics identify likely places of outbreak, drawing on to other kinds of information in the field of rainfall predictions, temperature forecasts, public health is also increasingly common. population density figures and local A study in Western Australia, for example, information on the quality of clean water looked at the impact of heat waves and found infrastructure. The algorithm projected with that age, socio-economic status, and whether 92% accuracy where cholera would break out. one lived in an urban or rural area were likely This allowed organisations on the ground to to affect whether people required medical engage in local education campaigns and pre- attention as a result of hot weather.58 Similarly, position medical supplies before the disease a large number of increasingly sophisticated appeared.60 efforts have looked for ways to deal with outbreaks of seasonal influenza, including the Advocates discuss a number of possibilities for use of mobile technology and Internet search precision public health in the future. The most information for disease reporting and tracking, commonly discussed possibility is so-called as well as genomics for vaccine selection. precision prevention, where the identification of genetic risk could be used to tailor Two of the most advanced examples of interventions for small sub-populations and precision public health involve the use of even individuals. In 2018, as part of a broader, analytics and geolocation for risk surveillance. five-year, £20.5bn prevention programme, A 2018 article in the New England Journal of the UK government announced that it Medicine and a 2019 article in Nature Medicine would be funding research into the use of published very detailed maps of Africa genetics and AI “to prevent people becoming showing progress against diarrhoeal mortality patients through personalised advice and and towards greater levels of breastfeeding, intervention”.61 To date, this remains an respectively. Both demonstrated that while unfulfilled ambition (beyond the long- the situation had improved in recent years, established ability to alert those with certain changes differed greatly both between and genetic mutations to higher cancer risk). within countries.59 This greater understanding of where health risks are situated should allow The causes of controversy more precisely focused interventions. While some see great promise in the potential In at least one case, geolocation of risk of precision public health, others view the almost certainly saved many lives. In 2017 idea with scepticism. The ongoing debate Yemen faced the world’s largest cholera highlights three important questions that will epidemic since records began. The following need to be answered if precision public health year, the UK’s Department for International is to become more widespread. Development used data analytics to help

How likely is it that precision approaches can increase one’s likelihood of cancer by will add value, compared with standard roughly 10%, but the “difference in polygenic practice today? risk scores [across the population] is much more modest. Where is the bar where you Perhaps surprisingly, critics and advocates of would change surveillance?” A broader precision public health have much in common concern is that data that becomes available when it comes to the question of value. may not necessarily be useful. Google Dr Khoury, for example, advocates for the inadvertently demonstrated this when it expanded use of precision public health but attempted to harness user search information also stresses the need for a strong evidence about symptoms to track seasonal influenza base to determine the value of specific outbreaks—an effort Wired magazine precision interventions, as would be done in described as an “epic failure”.62 This is not to any other area of medicine. Where the two say that all precision ideas will not work. To groups differ is in their degree of optimism date, however, the higher profile ideas have about the likely aggregate outcome of such yet to prove themselves. research. Critics also warn that efforts focused on It is likely that some precision public health personal prevention may be ill-considered. interventions will prove themselves while David Taylor-Robinson, professor of public others do not, and very few seem guaranteed health and policy at the University of to succeed. For example, Dr Williams—who Liverpool, notes that even with a wide range is no critic of precision public health—notes of evidence to draw upon, “the extent to that while polygenic risk scores have seen a which meaningful individual prediction is even lot of investment and are an interesting idea, possible remains unclear. The inconvenient they may not provide actionable results. He truth in the risk-prediction industry is that explains that certain genetic mutations, such we are predicting outcomes for groups of as the deleterious version of the BRCA1 gene, people like our patient; we are not predicting

the outcome for an individual.” A further as dominated by a focus on biomedical issues complication is that most non-communicable (in particular, genomics), in direct contrast to diseases (NCDs) are multi-factorial, which public health’s traditional emphasis on socio- means that genomic insights alone would have economic matters. Dr Taylor-Robinson, for limited predictive value (particularly as our example, expresses concern that precision understanding of other molecular-level data is public health seems to be “very much driven currently far less advanced). by the genomics angle, as far as I can tell,” while Dr Galea takes issue with “a notion that It also remains unclear if risk information at technology is a be-all and end-all solution the individual or small-group level will be of to the problems which face public health, much benefit, especially where the solution is when problems like clean air, a fair economy behaviour change. Dr Taylor-Robinson cites and gender equality are poorly served by several studies demonstrating that, in other technology”. contexts, knowledge of health risks does not greatly affect behaviour. Dr Williams has seen Dr Galea believes that this focus has a better outcomes—for example, over half substantial opportunity cost: “When tools take of patients in a study at Geisinger changed over and they become the end rather than the behaviour when told of individual genetic means, we make mistakes. It will be a net loss risk.63 However, the large number of people for all of us if there is a distracting investment who are overweight or obese in developed in these approaches at the expense of others.” countries, despite the well-known risks, Ronald Bayer, professor of sociomedical suggests that patient education will not prove sciences at Columbia University’s Mailman universally successful, even with individualised School of Public Health, agrees: “My main data. concern is that, because of a bandwagon effect, there will be a big investment in, and Does a precision approach change our shaping of, research that will shift the gaze of understanding of what public health those interested in population health so that means in ways that are misguided or they will focus on precision interventions.” harmful? He cites anti-smoking efforts as an example The second question about precision of where this would have negative effects: public health is whether the approach “The way we control the major morbidity and itself is fundamentally misguided. Here, mortality arising from tobacco is by limiting differences in opinion largely reflect different smoking. They are not going to be resolved by 64 65 understandings of how precision public precision medicine.” health works in practice. Those who are most Advocates of precision public health do sceptical tend to see precision public health not see the approach as inconsistent with

the traditions of public health, in large part precision public health is not largely about the because they disagree about the purported -omics, what distinguishes it from traditional dominance of genomics and biomedical public health approaches? Advocates argue sciences. Dr Khoury, for example, has always that precision public health is distinct, in that characterised precision public health as an it can provide tools to address many public extension of public health, rather than an health challenges more effectively. Others attempted replacement. He believes that “it disagree, arguing that modern public health is about much more than genetics. We should has been using increasingly sophisticated not lose sight of what we are trying to do at data and technology to understand risk and the population level, namely to use better and plan interventions since the birth of the field more precise data to target disease prevention (when John Snow mapped a cholera outbreak and control, and to improve health and health in London in 1854). Much of today’s output, equity worldwide.” In considering which data says Dr Taylor-Robinson, “is just public health to use, he continues, “social determinants are with better data”. Dr Bayer adds that, in many integral to precision public health.”66 areas, “‘precision public health’ represents a terminological shift, not a paradigm shift. This broader focus was reflected in the Targeting at-risk populations has always been Frontiers in Public Health 2018 special edition part of public health strategy. They now have 67 on precision public health. Of the 18 articles Big Data capacity to shape our understanding included in this special issue, only four related of where things are occurring.” Again, he sees to genomics (or other -omics). Of those four, a danger in allowing a “powerful conceptual two looked at questions that would need to domination that flows from medicine” to be resolved using traditional public health affect the broader world of health. approaches before such technologies could be used at scale.68 It remains unclear where precision tools are most likely to add value in public health, It is clear that precision public health is no whether they will distract from the mission longer predominated by genomics (if it ever and currently successful strategies of the was). What continues to divide people is field’s practitioners, and whether they will whether precision technologies will dominate cause a noticeable revolution that differs from or support work in the field in the coming the steady evolution of capacity in public years. health research. Keeping these issues in mind Is precision medicine really something will help to maximise our understanding of new or is it business as usual with slightly how to leverage the opportunities of precision better tools? technologies while reducing the risks.

The third question is related to the second: if

The challenges of integrating precision medicine into publicly funded health systems

Integrating precision medicine into health had still not been resolved. The number of systems is no small feat. As Dr Morrow articles on the difficulty of enacting change in notes, “for many GPs the whole concept of healthcare shows that his observation remains personalised medicine is, in many ways, alien.” accurate in the United States and many other Dr Dzau agrees, explaining that “the practice developed countries. As Dame Sally Davies of medicine has to change. That is one of the explains, “Generally, my tribe resists change.” biggest elephants in the room.” Second, precision medicine has made clear Three factors exacerbate this challenge. progress in specific areas of medicine, but First, healthcare systems have a particular it will only expand as potential benefits in immunity to large-scale transformation as a other areas become apparent. “The real result of their size, complexity, high levels of impediment”, Dr Dzau explains, “is that the regulation and large range of stakeholders. field is not there yet”. Indeed, two decades ago, the late Clayton Christensen, one of the world’s leading Finally, precision medicine will do limited good experts on disruption, wrote that “Health within traditional health systems. Kawaldip care may be the most entrenched, change- Sehmi, CEO of the International Association averse industry in the United States.”69 As of Patient Organisations, argues that this may recently as 2016, Mr Christensen told The represent the biggest change to medicine Economist Intelligence Unit that this problem since the founding of the WHO nearly 75 years

ago: “People haven’t appreciated the huge leap This begins at the top. Dr Williams observes from standard medicine which this represents. that “the biggest hurdle is for an organisation We need a new, unique precision framework to make the decision that this is important.” with the right institutions, policies, guidelines He notes that while US leaders in this and standards.” field, such as Geisinger and Intermountain Healthcare, have already made this decision, The expansion of precision medicine into “colleagues say that an important issue is to health systems involves a highly disruptive raise awareness in their systems that they institutional overhaul within a notoriously need to pay attention to precision medicine.” change-averse environment, all to create a Those not paying attention are currently in the system whose features are not yet fully clear. majority. A 2020 survey of American health As Dr O’Kennedy notes, this “change has to systems found that 70% described themselves be very carefully managed.” While a detailed as having low maturity in, or no use at all manual for careful management is well beyond for, precision medicine. 70 Strong leadership the scope of this paper, it is possible to identify characterises early adopters. For example, five key areas that will require attention: Dr Dzau notes that Qatar and the United stakeholder commitment, proof of value, Kingdom are making extensive efforts in this human capital, infrastructure and regulatory field, reflecting the conviction of political and environment. health system leaders that such investments 71 Stakeholder commitment will pay extensive dividends in the long term.

Healthcare providers Such convictions cannot remain isolated in senior management, however. They need to As with any change management effort, the percolate through the whole organisation, first challenge is securing an organisational where many people may remain sceptical. commitment to find the best ways to take “Culture and education are the big challenges,” advantage of precision medicine’s promise. Dame Sally Davies explains. Dr Qoronfleh

adds that “there is a bit of a continental divide” well disposed to cover some precision between those who see value in precision interventions, but this reflects hope for the medicine and those who do not. There is future rather than strong convictions about significant literature on winning the hearts and their cost-effectiveness. For example, a study minds of stakeholders within an organisation, of eight major European health systems found and the basic principles identified in this that they were willing to reimburse diagnostic literature apply equally to this challenge. To tests, but that this “was seemingly done cite just one example, Dame Sally strongly primarily to ensure access to the precision recommends using change champions to medicine and only secondary to the value they support a better understanding of the issues would provide”.73 The German government at play: “You need them. They play a big role.” has broken new ground by agreeing to fund Other elements of best practice will also need prescriptions for mobile phone apps, but each to play a role, including developing a coherent must prove its value in a limited time.74 strategic vision, building a clear roadmap for change and aligning incentives with the Payers appear more cautious in the United desired outcome(s).72 States. A recent survey found that while they were not averse in principle to funding Patients

Stakeholders outside the organisation also need to be on board, and the most important Leaping hurdles? stakeholders are patients. Daryl Pritchard, Barriers preventing adoption of precision senior vice president for science policy medicine (%) at the Personalised Medicine Coalition (a multi-stakeholder group supporting the Reimbursement / ROI 51 development of precision care), notes that Technology limitations 11 “you need patient empowerment rather than a paternalistic relationship with the physician. Clinical expertise 11 How do you get a patient involved in their care so they know they should get diagnostic Provider leadership support 8 testing that would drive more effective care?” Patient accessibility 8 (See the chapter on patient-centricity for further discussion.) Data aggregation / storage 8

Healthcare payers Viable outcomes 3 0% 20% 40% 60% Healthcare payers must also be committed to change. In Europe, health systems seem Source: Center for Connected Medicine and KLAS

precision interventions, they “will need with the promise of personalised medicine evidence of clinical utility to support coverage delivery.” Greater use of precision medicine and reimbursement”. 75 Many do not yet see will require the generation of more extensive such evidence. Indeed, a 2020 survey of US evidence of its value. health systems found that reimbursement issues were the dominant barrier to further Proof of value 76 adoption of precision medicine. Dr Dzau Evidence of value is clear in some instances, notes that US payers will drive more rapid such as the use of genome sequencing to adoption of precision interventions in areas diagnose rare diseases. In general, however, where their value can be demonstrated. robust studies of cost-effectiveness remain Payers are not alone in these concerns. patchy. The problem is not a lack of willingness The lack of answers to questions about to test new interventions, but rather a lack of cost-effectiveness and improved outcomes appropriate guidelines for doing so. Stefania represents perhaps the biggest weakness Boccia, professor of hygiene and public health for advocates of precision medicine as they at the Università Cattolica del Sacro Cuore in seek to win hearts and minds among health Rome, explains that “those who want to make stakeholders. Ms Dana notes that this is HTA [health technology assessment] reports “often the only kind of evidence a hospital for genomics or digital do not have agreed administrator or payer wants to see. There guidelines. Thus, in Europe there are very is frequently not enough evidence for a lot few. Without these reports, decision makers of them to be prepared to invest in new have difficulty knowing what to do.” A 2020 approaches.” Dr Pritchard agrees: “Healthcare review by the Personalised Medicine Special payers and providers want practice-based Interest Group of the International Society for evidence that will improve outcomes and Pharmacoeconomics and Outcomes Research lower costs. Since many of these technologies came to a similar conclusion when it looked are new, that evidence hasn’t yet caught up at the developed world more broadly: “Most

evaluation processes for precision medicines remain rudimentary for addressing evolving complexity in this space.” 77

Precision medicine presents many new challenges for traditional HTA procedures. One of the biggest challenges is finding ways to assess the value—in terms of cost, clinical outcomes, health system efficiency and patient quality of life—of the following:

• Diagnostics in general, including the impact of result accuracy on patients and health systems

• Diagnostics when applied to different inconsistency. In 2010 the manufacturer use cases, such as screening, treatment of the precision lung cancer drug gefitinib decisions or pharmacogenomics presented the same data to England’s National • Interventions that integrate diagnostics Institute for Health and Care Excellence and and treatments Scottish Medicines. The former estimated the cost per QALY gained to be £35,700 and • Next-generation sequencing, which might agreed to fund its purchase. The latter put the identify multiple therapies or diseases figure at £154,022 and rejected it. Although that were not tested for a dated example (the drug is now available in Scotland), this kind of disparity between • Drugs involved in so-called basket trials, precision assessments continues. Being able where the same medication is tested on to understand the true costs and outcomes multiple conditions that have a shared of disruptive innovation is an essential genetic attribute (to this particular prerequisite for the wider roll-out of precision challenge, add the problem of knowing medicine.79 which current therapy to compare the new one against) Human capital

78 • AI-based decision-support products If precision medicine is to reshape healthcare, Currently, a lack of expert consensus impedes health systems will need to develop workforce the wider adoption of precision medicine capacity, primarily through extensive interventions and creates substantial decision workforce training and improved medical

education. Dr Williams notes that finding The same is true elsewhere in the world. enough “trained genetic professionals is Experts in Europe report an existing shortage challenging because they are rare”, estimating that will only get worse as precision medicine that there are around 1,600 medical becomes more common.83 Similarly, in geneticists in total in the entire United States. Australia, Dr Gaff believes that as “a lot more A recent survey conducted in the United health professionals incorporate genetic States (the only one for which data is easily testing into care, it will not be possible for accessible) also found that the number of counsellors to be involved with all of those geneticists is not rising. Instead, the additional patients.” Dr O’Kennedy adds that these low work brought about by precision interventions numbers are not just an issue in themselves; is leading to longer wait times and higher they also send a problematic signal about job average patient caseloads.80 prospects. “If people are to make their careers in these areas, they need to know that there Genetics counsellors are also key players in will be jobs available,” he explains. the provision of precision care. This role often combines training in genetics and nursing Dr Gaff and others identify better training in (in many countries, a master’s degree) and genetics across the broader clinical workforce can involve various responsibilities, such as as an important part of the solution. In providing patients with information on the principle, this is not an unusual suggestion. reasons for genetic tests and the implications As Dr Morrow explains, “medicine changes of the outcome, as well as giving support to all the time. Every physician always needs clinicians who have less training in genetics. retraining.” The problem is the extent of Genetics counsellors are also in short supply, education that is required. Dr Radovich however. A 2018 study found that there explains that “existing health systems are not were just 7,000 genetics counsellors spread trained to handle” genomics and precision across 28 countries worldwide, and that medicine. Dr Qoronfleh reports that older around 4,000 of these were based in the clinicians in particular “don’t have the training United States.81 The US National Society and knowledge. It is a gap.” Furthermore, he of Genetic Counsellors believes that rapid notes that the places to which these clinicians proportional growth in the number of people may turn for insight also lag behind. Clinical in the profession is addressing the shortage. guidelines, for example, largely continue to be However, with slightly over 5,000 counsellors based on traditional medicine. Dr O’Kennedy in the entire United States—or around 1.6 per agrees that dealing with the very rapid 100,000 people82—it is hard to disagree with changes in this field is “crucial”: “Clinicians will Dr Williams’ description of these professionals need constant updating and older clinicians as “rare”. may not have received sufficient basic training to understand some of the information and its

implications. Fear based on lack of knowledge but two extensive international literature can create major impediments to adoption.” reviews found scant evidence on how to make these programmes effective at changing The problem is particularly marked at the clinical practice on the ground.86 primary care level, where various surveys reveal low levels of self-assurance among Human resource deficiencies also extend individuals about their capacity to understand beyond clinicians. Dr Khoury highlights that “a the results of—and in some cases, even critical workforce shortage ... in the application order—genetic testing. A survey reported in of mathematics and data science to life the journal Health Affairs found that 86% of sciences and healthcare currently exists.” general practitioners contacted in New York He adds that far too few people with the City lacked confidence in interpreting these necessary skills are available to manage and results. Although this percentage is unusually make use of large volumes of complex data high, a majority of primary care providers have from numerous domains.87 Health systems limited trust in their own ability to carry out that are serious about more widespread key elements of precision interventions.84 Dr adoption of precision interventions will need Qoronfleh is not surprised by these findings: to do better at finding new personnel and “The hurdles include the vast complexity of training current ones in the necessary skills. the science, and the need for physicians to learn about a significant range of new tests Another human resource issue that is likely and novel ways to counsel patients through to prove equally important has received probability-based decision-making.” even less attention: how effective precision medicine will inevitably reshape patient– Dr Qoronfleh notes that “modernising medical clinician interactions and demand the curricula and medical school instruction is provision of resources so that healthcare critical,” but progress to date has been slow. providers can spend more of their already Ms Dana reports that “genomics does not get limited time with patients. Precision medicine much coverage in medical curricula,” and the will present substantial time challenges data bears this out. In the United States, for for clinicians, especially generalists (in the example, the number of genetics programmes absence of sufficient geneticists and genetics in medical and nursing schools has been counsellors). At the primary care level, for growing, but a recent expert editorial noted example, doctors will need to educate that “the actual number of learners in these patients in new fields that are relevant to their ... is dwarfed by the number of non-genetic care, such as genomics—areas where they health-care professionals in practice.”85 For frequently lack confidence. If doctors are to those already in practice, various training order genetic tests as part of their day-to-day programmes exist across developed countries, clinical work, they will also need to devote

more time to ensuring that patients have given constraints of primary care.” (He adds that informed consent.88 (As discussed in the next more accurate diagnosis and treatment may chapter, this is more complicated than for perhaps eliminate some of the time required many current medical interventions.) Finally, a in today’s trial-and-error approach.) This learning health system—the goal of precision highlights that health systems adopting medicine—will also require ongoing changes precision medicine will have to rethink care to best practice in care, and at a faster rate pathways and provide clinicians at all levels than currently occurs. with the necessary time to carry out their revised roles. For Dr Ginsburg, this raises an important question: “How does a generalist have a Infrastructure legitimate patient-centred conversation, when you have 15 minutes to assess, make a Precision medicine requires substantial decision and get on your way? We don’t have infrastructure above and beyond what is a paradigm to really engage the patient in needed to support current healthcare. In the ways that are needed to make precision such a data-dependent enterprise, the ability medicine impactful for them.” Dr Morrow to collect, store and analyse a vast array of agrees. “The big challenge”, he says, “is that it possibly relevant information, and to then is relatively easy to do traditional medicine feed any insights into the health system, is because it is standardised and can almost be of fundamental importance. Some countries semi-automated. Also, at current levels of have taken substantial steps in this direction, resourcing, that is what can be realistically but none are there yet. achieved. To move to genuine precision QUT’s Matthew Bellgard explains that the data medicine will require a more personalised necessary for precision medicine is generally approach for many of the discussions, which “fragmented, and housed in multiple disparate will require more time. It is hard to see how data repositories, be they spreadsheets, that will be achieved within the resource registries, longitudinal databases or paper-

based notes”, adding that “there is an Even in leading areas in precision medicine, urgent need for cross-jurisdictional data such as cancer care, data is not yet available governance and standards harmonisation.” in a format that allows analytic tools to use it LifeOmic’s Dr Brown notes that “the first reliably for complex purposes. IBM’s much- hurdle [in implementing] precision medicine is heralded Watson Oncology Expert Adviser, for aggregating all that data in some sort of useful example, was unable to recognise important way.” Dr Bilkey agrees: “The biggest challenge details from patient files such as stage at is collecting the right data and linking it to ask diagnosis and therapy history timeline.91 While meaningful questions without compromising oncology is well ahead of other medical fields, privacy. Adequate computational it may still take the better part of a decade to infrastructure is a big issue.” Developing this work through the issues involved in getting infrastructure, she adds, “is still a work in reliable, well-labelled data.92 progress”. One sign of this data dearth is the substantial Amid the excitement about precision interest that high-quality data attracts. Dr medicine, it is worth noting that health Gebo explains that within three months systems and researchers are both in the very of the All of Us programme launching the early stages of obtaining and organising the beta version of its Researcher Workbench necessary data. A study published by the in May 2020, 100 institutions had signed up Organisation for Economic Co-operation for access, even though genomic data was and Development (OECD) in late 2017, for not yet available. Similarly, in May 2020, example, found that while EHRs had become Nature’s editorial focused on a series of much more common across all countries, articles looking at genetic variation based only ten of the 28 member states had the on 15,708 individual human DNA sequences necessary technology to support “health and 125,748 exomes, heralding this as “the system quality, efficiency and performance most extensive publicly accessible analysis and create a firm foundation for scientific carried out so far” and describing the amount research and discovery”.89 Persistent problems of data as “staggering”.93 These are important include a lack of validated, high-quality data; developments, but they are far short of the poor interoperability in data systems, even vision of nearly unlimited data, gathered from within countries (let alone internationally); a vast range of sources. insufficient data infrastructure to gather and analyse the necessary information to better These data issues will not fix themselves, inform their own activities; and the continuing, but proof of value is required to address the widespread storage of healthcare information various challenges. As a recent essay in NPJ in unstructured ways, including on paper.90 Digital Medicine explained, “In spite of the widely touted benefits of ‘data liberation’, a

sufficiently compelling use case has not been study concluded that “The clinical diagnostic presented to overcome the vested interests testing landscape is broken.”97 If precision maintaining the status quo and justify the medicine is to become better integrated into significant upfront investment necessary to the health system, this landscape will need to build data infrastructure.”94 Until this use case be fixed. Efforts to integrate genomic testing has been developed, the ability of precision into NHS England provide examples of the medicine to deliver on its promises will be kind of changes that are required (see the highly constrained. box on mainstreaming genetic testing in NHS England). Another essential element of precision medicine infrastructure is sufficient laboratory testing capacity, given the large number of diagnostic tests involved, and in particular next-generation sequencing. According to a study by Diaceutics, a diagnostics company, biomarker tests are only offered in enough facilities to benefit the optimal number of patients 1.5 years to 5 years after the launch of the relevant treatment. The study identifies various reasons for this. Some of these reasons involve clinicians, but others are lab-related problems, such as low levels of test availability, reliability and speed.95 An increasing demand for tests will also exacerbate current workforce shortages in many developed countries.96 The Diaceutics

Making genetic testing mainstream in NHS England

In 2017 Dame Sally Davies, then chief local funding and academic interest. She medical officer of NHS England, issued an adds that this uncoordinated network is “not annual report entitled Generation Genome, the way to deliver the best national genomic which called for the integration of genomic service. You need centralised laboratories. medicine into the service’s standard care.98 They are the state of the art because of Such a transformation takes time. In April throughput and cost-effectiveness.” 2020 the NHS rolled out the Genomic Medicine Service, but health officials do As with many health system changes, the not expect genomic medicine to be part interests of current stakeholders had to of routine care until 2025. For healthcare, be addressed, including the interests of this is a respectable pace of change. As people managing existing laboratories. Dame Sally notes, “we have started really The result was a compromise, with the well and have a lot to be proud of, but creation of seven supra-regional laboratory we are not there yet.” A number of issues hubs (although some tests requiring around “democratising” genetic laboratory specific expertise are conducted by a more testing—that is, making it part of the routine limited number of National Specialist Test care provided to every patient, where Providers). Dame Sally explains that she appropriate—illustrate some of the practical “would have liked to see more consolidation, considerations involved in the necessary but [having seven hubs] meant that we took reshaping of existing health infrastructure people with us”. and practices. Another fundamental requirement for Within Generation Genome, Dame Sally the democratisation of genomic medicine Davies called for a new kind of laboratory testing has been to make clear who inside infrastructure, part of which involved the health service can order such tests, expanding the kind of expertise and and when. Accordingly, the National 100 tools available. The report said that the Genomic Test Directory lists the tests required facilities would need “high- covered by the NHS, and the symptoms powered computing, not banks of test- associated with ordering those tests. It also tubes”.99 Another necessary change was indicates the kinds of clinicians who can more structural: a shift in the number and order different types of test. At present, capacity of laboratories. At the time, Dame the directory is largely dedicated to rare Sally says, a kind of “artisanal, cottage diseases and cancer, but it is expected industry” of multiple facilities existed. to expand to cover more conditions in Their locations and areas of expertise did greater depth as research develops relevant not reflect a thoughtful distribution of assays. Although Dame Sally acknowledges resources, but rather were influenced by the limitations—and would prefer more

whole-genome sequencing and fewer point outcome code, along with the detailed tests—she believes that “we are one of the results. Depending on the reason for only countries that has such a directory. It is the investigation, these codes convey really special.” information such as “Diagnosis Consistent with Referral Indication”, “[Tumour] Variant With a specialist laboratory network and Detected – Response to Targeted Therapy, this directory, non-geneticists will be Prognostic/Actionable” and “Actionable able to order a growing number of tests Pharmacogenomic Variant Detected”. for an expanding array of conditions. In order for these new tools to provide As NHS England’s efforts demonstrate, value, the complexity of interpreting the getting the organisational arrangements in results needs to be kept to a minimum.101 place is often as important as the science Accordingly, the new NHS Genomic Testing behind the medicine. Reporting Specification102 requires that the ordering clinician receives a brief test

Regulatory environment

Without actively seeking to enable precision medicine, healthcare regulation will almost certainly impede it. The existing and typically extensive regulations that exist in most countries are designed to support the old way of doing things. As a result, they could block possible innovations, such as using AI to identify the best treatment or basket trials for multiple cancers that share a common mutation. Government policymakers who wish to enable wider use of precision medicine will need to create an appropriate regulatory environment.

Drug approval bodies in many developed been looking for ways to modernise clinical countries have already taken substantial steps trial design, including increasing the use of in this direction. The US FDA, for example, has basket trials, umbrella trials (trials of multiple issued various guidelines on the diagnostic drugs, or combinations of drugs, compared use of next-genome sequencing. It has also side by side), real-world data, and smaller

trials with more defined populations, all of There are greater concerns around AI which can expedite the approval of certain and data. In 2020, for example, a WEF precision medicines. The European Medicines report found that there “are no common Agency (EMA) has been working on similar frameworks for the privacy and ownership issues, often in co-operation with the US of precision health data”.104 The regulation FDA and other major regulatory agencies. of AI within medical devices also faces a Looking ahead, the EMA’s 2020-2025 strategy host of unresolved challenges. One such document lists as its top human medicine challenge is transparency, as many AI tools priority “catalysing the integration of science cannot explain why they are recommending and technology in medicines’ development”. a particular course of action (which runs This priority largely consists of goals that contrary to medical ethics). Another challenge explicitly and implicitly seek to support the is continuous adaptation: as the AI learns more development of precision medicine.103 This and its recommendations change, will they focus helps to explain the high proportion still be safe and appropriate? A third challenge of newly approved drugs that are precision is whether the data that AI uses to learn medications. is of sufficient quality, or is representative enough of the patient being treated to provide accurate advice.105

Getting more personal Major regulatory bodies such as the US FDA Percentage of FDA approvals relating to and the EMA are wrestling with these issues, personalised medicine (%) but the answers will not be easy to find. Until these issues are resolved, data analytics’ 50 contribution to precision medicine—and with 42 40 it, much of the field’s promise—will remain 34 limited. These efforts will also be complicated 30 28 27 by some of the thornier ethical questions 25 20 21 related to precision medicine, which are discussed in more detail within the context of 10 patient-centricity in the following chapter. 5 0

2005 2014 2015 2016 2017 2018 2019

Source: Precision Medicine Coalition

Patient-centricity: The essential complement to precision medicine

The advent of precision medicine is not the • Access to high-quality care only tectonic change that healthcare has been experiencing lately. As Dr Ginsburg explains, • The recognised status and authority of “in general, up until the last 15 years or so, patients, families and carers within any medicine has been an incredibly paternalistic health-related activity, so that they are profession. It is not just precision medicine; co-creators of healthcare with medical the entire field is shifting to understand the personnel patient and his or her priorities and needs.” • Processes and mechanisms built into the This shift away from paternalism has been system to support patients, families and 106 driven by the advent of patient-centred care. carers in taking on this co-creator role Again, there are competing definitions of Rather than viewing patients as objects of what is meant by “patient-centred”, coupled solicitous care, or even as an empowered with a lack of agreement regarding specific consumers, they are seen as full and active terminology (for example, the WHO prefers partners with clinicians. This partnership “person-centred” to “patient-centred”). A 2019 includes decision-making about an individual’s Economist Intelligence Unit study reviewed treatment, and, to the extent possible, the many definitions and found three common co-creation of health research activities elements that are key to patient-centred care: and patient input into the management

of healthcare systems. This patient- Mr Sehmi agrees, describing “a lot of centred approach has won the intellectual confusion. People seem to forget patient battle in most health systems and in the engagement when they talk about precision pharmaceutical industry; the challenge is to medicine because the technology overwhelms translate this approach into practice.107 it. The shiny part takes over, and they forget the complex human mixture of emotions Integrating precision medicine and and frailty that somehow does not fit in.” This patient-centricity confusion is dangerous, warns Nancy Kass, It is important to distinguish between patient- professor of bioethics and public health at centricity and precision medicine. Perhaps Johns Hopkins University. “Patient-centred because of the lack of accepted definitions care looks at the whole person, including for the two terms, Alan Balch, CEO of the habits and values,” she says. “You will probably National Patient Advocate Association in the get better medical outcomes from that than United States, sees a “risk that people may from just sequencing a genome. My biggest assume that precision medicine equates to fear from precision medicine is doctors and patient-centricity, and if you are offering the patients putting far too much emphasis on it one you are also offering the other”. Indeed, as a panacea.” the ideas are sometimes conflated, with When both are understood properly, however, people assuming that precision medicine patient-centred care and precision medicine will be patient-centred simply because it can reinforce each other. As Dr Dzau explains, looks closely at each individual’s data or “precision medicine, if done right, is totally 108 characteristics. aligned with patient centricity.”

Such thinking mischaracterises patient- What does this look like in practice? centricity. Mr Balch explains that patient- centred care is not just about finding a In a patient-centric approach, clinicians, genetically or immunologically appropriate patients and other relevant stakeholders medication, but rather is a comprehensive share information to help reach agreement process through which the patient and on the best way to deal with a given issue. clinician collectively decide on an evidence- Medical professionals typically contribute based course of care, informed by the expert insights on constraints and choices— patient’s unique attributes and preferences for example, the nature of a health condition that will impact health outcomes. Precision or risk; different ways in which it may be medicine may be applied as part of this addressed; and the implications of those process, but the process may also lead to no options, such as the probability of clinical medical intervention at all. success or side effects. Patients bring details

about the kind of outcome(s) they value most, treated is happy [with the option] and comes based on what is important to them. This in the right frame of mind”. search for value can go well beyond traditional medical matters. “I might want an Alzheimer’s Advances in precision medicine do, however, Disease test, not because of any clinical action affect the role of both partners in several I can take, but to be able to change my plans ways. Clinicians will require education about for long-term care,” Dr Ginsburg explains. the general public and their role as patients. If patients do not understand how precision Mr Sehmi notes that precision medicine does medicine works, they are unlikely to ask not fundamentally alter this partnership. about how it might apply to their situation. Instead, it adds to the available options that Dr Morrow says that the kind and degree of are included in the conversation. Patients expertise that patients expect from clinicians and clinicians should consider a precision in patient-centred relationships is likely to intervention near the start of their interaction, change. Precision medicine will vastly increase rather than the clinician assuming that it is the amount of available and potentially the best option. Dr Williams explains that at relevant data and provide a host of valuable Geisinger, “the engagement piece up front is new insights, which will simultaneously create critical. You have to ask what it is that you, even more extraneous information that needs as a patient, want to accomplish from this to be stripped out. “The biggest challenge in care episode. Genomics is a new shiny toy in translating this amazing science into a person- the medical armamentarium, but not every centred framework”, Dr Morrow continues, “is question has a genomic answer. Don’t try to that the presentation of highly complex data impose one on a situation that does not need has to work at a physician level and a patient it.” Mr Sehmi uses the analogy of a spear: level”. precision medical science may be the tip of the spear, but the shaft is just as important, At the same time, Dr Brown explains that which involves “making sure the person being patients will gain much greater control

over how they obtain information about themselves, independent of traditional healthcare providers. He expects that technology will allow a “decentralisation of healthcare. Rather than go to a clinic, hospital or doctor’s office, we will be able to do laboratory assessments of our bodies in our own homes and have the data analysed.” As discussed earlier, consumer wearables are also likely to provide a plethora of potentially relevant lifestyle information. Determining how to use and regulate this kind of data remains a matter of debate, but it is clear that the patient–clinician partnership will move even further away from one where the Co-creation and collaboration clinician decides what information matters to their conversation.109 Aligning patient-centricity and precision medicine is not simply a matter of finding the This does not eliminate the need for a patient– best treatment for individuals. It must also clinician partnership. In many cases, patient- involve the co-creation of the research and provided data—including data that can only analysis that is an integral part of precision be provided by the patient—can be valuable medicine. The pharmaceutical industry is to all parties. Dr Ginsburg cites a web-based already seeing the benefits of working with questionnaire on family history at his clinic patients as partners in drug research and as an example of how patient-provided data development,110 and Mr Sehmi believes can be used to inform and enhance patient– that the analytical tools applied to further clinician precision medicine discussions. precision medicine will also require patient Once the patient has entered the relevant involvement: “You can’t expect a patient- data about the health conditions of various centred response from a computer unless you ancestors and other relatives, software uses have programmed it to be patient-centred. a series of decision-support rules to analyse AI and machine learning tools will often miss the information and make recommendations. out cultural differences. Being culturally These are put into a report sent to both the competent requires a lot of understanding clinician and the patient, who can then discuss from all those involved. Otherwise, the wrong the information in more detail when they next choices will be made.” meet.

Mr Balch adds that when AI is useful for right words are there, a lot of the time, the understanding a medical situation, it should real partnership is not.” The issues are often include the most robust variables that not related to science. As Dr Dzau highlights, are relevant to patients. These should go resolving questions around transparency beyond clinical outcomes to include data and the democratisation of information will sets related to how an intervention affects be crucial to achieving alignment between issues such as employment or the ability to patient-centric care and precision medicine. live independently. “There is an opportunity This requires consideration of the potential to wrap data collection and AI around these contribution of patient-centred care when matters,” he continues. “Then you can move addressing ethical matters associated with into a care-planning mode that helps patient precision medicine. and clinician understand when they might expect to see these types of other socio- Viewing ethical issues associated with economic barriers to healthcare access and precision medicine through a patient- affordability and talk about what to do.” centred lens Dr Ginsburg does not see this breadth as Many of precision medicine’s biggest ethical changing the aims of precision medicine. issues are far from new. Informed consent Rather, it is about enabling precision medicine and patient privacy, for example, are long- to do what it should always have aspired to: standing concerns in healthcare. However, “At its core, it should take into consideration the advent of widespread precision medicine all aspects of the patient, including their is adding greatly to the complexity of these priorities, social determinants and family issues. One driver of these new complications history.” is the permanent nature of an individual’s Achieving this vision of patient-centred genetic data and the potentially vast amount precision medicine remains a work in progress. of information that can be derived from it. Dame Sally Davies notes that “even where the Said Ismail, director of the Qatar Genome

Programme, explains that “When you do not.” At the same time, it seems inappropriate whole-genome sequencing, you are not just to not be able to tell a patient that they are at targeting one gene or one disease. Genetically, high risk of a serious condition where a clinical the individual is an open book for you.” response is possible. The European Society of Human Genetics and the American Society of This breadth of detail creates the possibility Medical Genetics take different views on this of incidental findings, which may become matter. The latter maintains a list of genes that apparent at the time of the original should be reported to the patient when found laboratory work, or possibly years later as incidentally; the former stresses the need to our understanding of genetics improves inform the patient of the issues before the (assuming the patient’s DNA is kept on file). test and take into account the possibility of Where people have given their genomes on incidental findings when deciding whether to a voluntary basis to databases before they use a whole-genome sequence.111 are patients, Dr O’Kennedy notes that this “represents a significant trust. It is literally a A change in how health systems operate life-long commitment.” Deciding what to tell in an age of precision medicine will bring a patient about an incidental finding is not further ethical challenges. Dr Ginsburg notes straightforward. In some cases, the patient that these systems will need to be “learning may not want to know. For example, Dr health systems, so that in the course of care Morrow explains that “a significant proportion we gather data and generate evidence. They of people at risk of Huntington’s Chorea should be where care is given, and research choose not to have the relevant genetic test. done.” The blurring of these two activities They would rather live with uncertainty, which has important implications for the meaning allows them to function and manage the risk of consent. For example, a whole-genome and their lifestyles in a way that works for sequence taken in search of information on them.” If autonomy matters, he continues, a single condition could potentially lead to doctors need to respect those sorts of wishes. database discovery of other health related findings.As a result, Dr Afifi believes that However, as Dr Ismail adds, “the thousands “the main ethical concern [around precision of mutations where [genes may show a medicine] is consent.” Even asking for consent risk, but] the science is not yet clear cut?” in this context is far from straightforward. Ms Complicating matters further is the extent Dana explains that such “information is deeply of shared genetic heritage within families. As personal. If you consent to have it collected, Dr Nahla Afifi, director of the Qatar Biobank, are you consenting for your children and explains, “families can be affected by one relatives? These are not questions normal person’s genetic findings. Within the same consent processes cover.” She adds that family some may want to know, some may

there are further challenges if genetic sample communities in developed countries—a collection involves working in less developed perennial issue for health researchers—will be regions of the world, where “often the equally important. language does not even exist for this kind of conversation. The word ‘gene’ might not exist Finally, while diversity is essential for accuracy in the local language.” in precision medicine, it can also complicate how health systems address ethical concerns. The storage of genetic data also raises privacy Scientists and religious leaders, for example, issues. Mr Sehmi explains that patients do not often have different attitudes towards want medical data being used against them— precision genetic medicine, and attitudes may for example, at a traffic stop or when applying also vary across and within different religions. for life or medical insurance. As a result of These attitudes are not necessarily in conflict, such concerns, patient information included in but they may inform different perspectives large databases is typically anonymised. That on ethical issues.112 Dr Qoronfleh explains that said, it may be possible to de-anonymise this “you cannot underestimate” the importance information in the future. Professor Kass notes of different faith and cultural traditions that “we used to say that we could guarantee when considering questions regarding the the anonymity of blood samples. Now, we implementation of precision medicine. can’t really do that when a scientist can do certain analyses. It is not that the original How patient-centricity can help researchers were dishonest. Instead, science Patient-centricity does not unilaterally has evolved and certain information about us resolve these challenges, but it is an is unique and in our blood.” essential component of the solution. An Informed consent also has to be obtained enriched discussion about a given precision in a way that allows data collection from a intervention, for example, should cover the suitable range of patients. Professor Kass ethical matters related to data. Patients should explains that “certain kinds of databases do be told about the possibility of incidental not reflect the heterogeneity of the whole findings prior to testing, enabling medical population. Sometimes that is fine, sometimes teams to learn from each individual in their not. If databases used for predictive modelling care what he or she wants to occur if such a are not as heterogeneous as a population, discovery arises. There is no reason to impose inappropriate inferences may be made.” Part a one-size-fits-all policy here, especially when, of the solution to this particular challenge as Mr Balch puts it, “precision medicine is is the large databases being put together in about creating appropriate variations in care countries such as Qatar, Turkey and China. based on evidence.” Dr Morrow agrees, noting Engaging with potentially distrustful minority that respect for autonomy, except in very

rare circumstances, means letting the patient concerns of many when she notes that “we will choose, even if a given decision is “at odds only get [the] most from precision medicine with traditional medical frameworks”. With so if we can share and learn from data. If people much data being held on a patient, including have difficulties with data sharing, it is a their wishes on matters such as incidental potential problem.” Here, a patient-centricity findings should not be difficult. can again smooth the way. Mr Balch explains that people are much more likely to share data The way that any information might be if patients are co-creators of the research or stored or used should also feature in the can be part of the learning experience. “If you discussion, and any privacy concerns should create a value proposition for patients”, he be addressed. Mr Balch recommends that says, “if they understand that the data being people should have to opt in to contributing collected are relevant to their care and can their medical information to larger databases. help others, people will be invested. If you put This approach is highly unlikely to undermine the data in a black box and they never see how patients’ willingness to share data, as most it is used, they are less likely to understand the patients are already inclined to do so. Surveys value.” show that majorities in various countries are willing to share with researchers medical Patient-centricity is also likely to help ensure and lifestyle data that is relevant to health, that databases are sufficiently diverse and although factors such as the precise nature of represent the population as a whole, as the the information and whether the research is All of Us programme is finding (see the box on conducted for profit do affect decisions to an the All of Us programme). Lack of diversity is extent.113 Some individuals do not even wait a long-standing problem in medical research for academics to contact them. For example, and could undermine the ability of precision around 6,000 people have made the results medicine to help large sections of the of their own commercial DNA sequencing population if it is not appropriately addressed. available in a public database, OpenSNP. This willingness to share data is consistent with Finally, in a truly patient-centric conversation, the experience of experts interviewed for patients, their families and their carers bring this paper. As the Australian Genomics Health with them their religious and cultural views. Alliance’s Dr Sinclair explains, “if people are This allows clinicians to understand what sick, they don’t care that much” about these constraints, if any, these views might impose issues. on precision interventions, and how these might be best addressed on a case-by-case Nevertheless, willingness to contribute data basis. is not universal. Philippa Brice, external affairs director of the PHG Foundation, expresses the

All of Us: Bringing diversity and patient partnership together

The demographics of individuals who participate in medical research do not Dedicated to diversity reflect those of the general population Race and Ethnicity of All of Us enrollees to in much of the world. The disconnect is 24 September 2020 (%) probably most studied in the field of clinical White Asian Black, African-American trials in the United States. A 2018 article, or African for example, looked at ten trials held in the Hispanic, Latino More than one race or Spanish or ethnicity three preceding years for drugs to treat cancers that predominantly affect black Other Prefer not to say people. The research found that white 50 people were the largest group of patients 46 represented in the research.114 40

Dr Ginsburg,reports that this is a problem 30 22 within current databases available for 20 18 medical AI. “What is missing”, he says, 10 “would be diversity. We have poor 6 3 2 representation of ethnicities from outside of 0 1 those of European ancestry.” This statistical issue has important health implications. For Source: All of Us those whose ancestry is less represented, adds Dr Ginsburg, “the chances of misinterpretation are high.” Race is not the research process, lack of information only issue; women and older people are also about the study and its potential value, less represented in many databases. and the time and resources needed to take part.115 All of these issues reflect a frayed Although the general problem of under- relationship between researchers and representation of certain groups in study participants, who, in the words of one research has long been recognised, respondent, are wary of being treated like progress to address it has been slow. This “guinea pigs”.116 The study warned that no is not necessarily an issue of researcher single intervention could solve the problem. negligence. A study that looked at the problem for clinical trial researchers found One aim of the All of Us research that leading barriers to greater inclusion programme is to address this research of a variety of racial and ethnic groups disparity. Dr Gebo, the programme’s included mistrust of the process by under- former chief medical and scientific officer, represented groups, discomfort with the explains that they wish to create “a

research platform with a wide variety of have a trusted relationship with groups that populations, including those who have not are under-studied”, says Dr Gebo, “it will been traditionally included in biomedical help you understand what participants are research studies before”. Accordingly, the doing by donating data [i.e. the emotional programme is trying to collect data on a commitment behind it] and they will trust disproportionately high number (compared the research you are doing.” This in turn will with the general population) of individuals lead to greater levels of participation and from such groups, including ensuring that engagement. over half of its participants are from US racial and ethnic minorities and 80% are Outreach to community leaders must be from any understudied group, such as older accompanied by efforts to build strong Americans. So far, it has met these goals.117 relationships with the individuals involved in the study. This begins with enrolment, with Correcting under-representation of these most people entering the programme via populations is not simply a matter of in-person recruitment sites. Once enrolled, sending circulars to minority individuals. the status of participants within the joint It has required the All of Us programme effort is critical. Dr Gebo explains that “one to find ways to establish strong, trusting of the most important lessons we have relationships with minority communities learned is the value of partnership. We view and individual participants. For example, it participants as partners: they help us think has worked with black churches to explain through questions like what data we should the programme to their members, and collect and how, what types of research it is relying on clinicians in a number of questions they would like for us to address, Federally Qualified Health Centers to reach as well as which researchers we should aim individuals from lower socio-economic to have. There is nothing like talking with backgrounds (rather than simply recruiting a participant who says this is what you are through academic medical centres, as many doing wrong and this is how to fix it.” These trials do). The programme also has a Tribal interactions bring clear practical gains in Collaboration Working Group, composed understanding how to structure research, of tribal leaders, researchers, institutional but they also create a sense of purpose. As review board members and community Dr Gebo notes, working with participants members, to support work with American as partners “drives home to us why we are Indian and Alaska Native populations. “If you doing the work we are doing”.

Patient-centricity can help to address the ethical challenges associated with precision medicine by transforming healthcare from a transactional activity to a relationship between the various stakeholders, especially the clinician and the patient. In doing so, it can engender trust. Without this, says Dr Dzau, precision medicine will not deliver on its promises. “The public and patients need to feel that they own this approach. It is so important to gain their trust,” he explains. Dr O’Kennedy agrees: “Trust is essential when you are looking at this. It is something we all have to learn more and more about.” This highlights that patient-centricity is not a complication for those seeking to use precision medicine; rather, it is an essential part of making it work.

Turning a vision into reality

The possibilities of precision medicine are Aid workers have even been able to predict compelling. Rapid changes in the volume and and prepare for cholera outbreaks. nature of available data, and in our ability to store, access and analyse that data, could While it is important to acknowledge and collectively move healthcare towards what celebrate this progress, one must also has always been an unstated and unattainable acknowledge the limitations in the field. To aim: delivering the right intervention to the date, precision medicine has tended to deliver right person (or population) at the right time. gains in very specific areas, primarily where Achieving this would mean that patients genomics play an extensive role in how bodies, receive far better treatments, health systems tumours and pathogens act. The promise of become far more effective and populations individualised care, informed by a wide range become far healthier. of molecular and lifestyle information about a specific person, remains a distant goal. So, too, Precision approaches are already bringing real does the broader transformation of medicine benefits. In some cases, doctors have a much from what can be an art of trial and error to a greater ability to prescribe the correct drugs precise science. right away, rather than using trial and error to determine which option (if any) works best. The broader integration of precision medicine Previously undiagnosed rare diseases are into healthcare (beyond specific genomic being identified, and patients with potentially applications) will happen quickly, but it will fatal cancers are now experiencing greater life require a supporting infrastructure that differs expectancies, and in some instances cures. from existing health system infrastructure

in most countries and in various ways. No highly successful in meeting the needs manual exists for those seeking to bring about of patients and populations. The sector’s this change, but experience to date suggests aversion to risk is a change management that the following recommendations will be challenge, but it has laudable roots. “First, useful to keep in mind. do no harm” is inculcated into clinicians in part because most can cite examples of First, those who are interested in enabling the innovations that fell flat. Too great a focus expanded use of precision medicine need to on precision medicine has the potential remain focused on why they are pursuing this to undermine what current arrangements goal, even as they struggle with the “how”. already provide, and any innovation needs As the debate around precision public health to avoid hurting effective processes that illustrates, two broad questions are central are already in place. to determining whether the effort to use precision approaches is worthwhile. They are, Second, efforts to increase the use of in some ways, two sides of the same coin. precision medicine must address a wide range of practical issues, including those listed • Is the effort worth the added value below. that precision medicine may bring, compared with current practice? The • Securing commitment: Advocates of answer to this question is likely to vary precision medicine within health systems across different areas of healthcare, and and healthcare organisations will have over time. In some areas, the answer to dust off their change management will be a resounding “yes”, but in others textbooks. The most pressing need the potential benefits may be small. This is to secure the commitment of top suggests that precision medicine will be management, the organisation as a introduced in a piecemeal manner, at whole, and other key stakeholders such as least initially. As more and more fields gain patients, payers and regulators. access to newly created infrastructure and enhanced workforce skills, it is likely • Proving value: At present, there is that an increasing number of beneficial insufficient evidence to demonstrate that uses will become apparent. precision medicine provides improved outcomes in cost-effective ways. Any • If precision medicine represents new way of doing things has to be able a significant shift within a specific to show hard evidence of its advantages medical field, is that change over existing approaches, not merely to misguided? Even without precision win over sceptics but to justify greater medicine, modern healthcare has been deployment. HTA bodies in particular will

need to develop agreed ways to measure central to precision interventions are such value. not being rolled out quickly enough. Laboratories are frequently stretched • Developing relevant expertise: Medical and understaffed. Health systems and schools and health systems need to laboratory service providers will need train up more clinical geneticists and to build centres of excellence to ensure genetics counsellors. An understanding of speed and quality. genomics, and eventually other aspects of precision medicine, also needs to be • Putting in place regulation that inculcated in the medical workforce. reflects how precision medicine is done: Regulation needs to keep • Providing clinicians with appropriate people safe in a way that does not block time and resources to engage in innovation. Leading drug approval precision medicine: Current resourcing agencies have been taking steps to levels reflect what is needed to deliver achieve this for precision medications, traditional medicine. The necessary and this kind of change must continue. investment to roll out precision medicine Health system regulators will also need to must include the required time and wrestle with how best to regulate AI tools. money for revised clinical pathways and clinician–patient interaction. • Working with patients as full partners in all the changes that are needed to • Getting data into shape to provide bring about precision medicine: Patient the necessary insights: The vast co-creation will focus precision medicine amount of data that already exists within on the issues that can provide the most health systems—along with any relevant value to patients. It is also likely to reduce information produced outside of those the ethical challenges that will arise from systems—remains largely unready to the new kinds of healthcare data and provide the insights on which precision analytical tools that become available. medicine will rely. Large health systems, This will require both new attitudes within healthcare providers, information health systems and more extensive basic technology companies and regulators will education of the population about how need to continue efforts to turn today’s precision medicine works. disparate information into something that is genuinely useable at a large scale. We are still in the early stages of learning how to implement precision medicine and • Strengthening laboratory testing understanding what this will look like in infrastructure: In many countries, practice. All relevant stakeholders need to the diagnostic tests that are currently

ensure that they develop the appropriate and necessary foundations for precision medicine in order for this radically new way of doing things to deliver on its promises.

Endnotes

1 Definitions of precision medicine are discussed later in 9 “Organizations See 878% Health Data Growth Rate the paper. Since 2016,” HIT Infrastructure, 8 May 2019, https:// hitinfrastructure.com/news/organizations-see-878- 2 The term precision medicine has been used more health-data-growth-rate-since-2016 frequently in US discussions in recent years, following its adoption in a 2011 National Academy of Medicine study. 10 IDC, The Digitization of the World From Edge to Core, In preferencing the term precision medicine, the authors https://www.seagate.com/files/www-content/our-story/ sought to avoid any connotations of individualised trends/files/idc-seagate-dataage-whitepaper.pdf treatment arising from use of the word “personalised”. However, it should be noted that they used an older 11 National Human Genome Research Institute, “DNA definition of personalised medicine to describe precision Sequencing Costs: Data,” web page accessed 10 August medicine. See: National Research Council, Toward 2020, https://www.genome.gov/about-genomics/fact- Precision Medicine, 2011, https://www.ncbi.nlm.nih.gov/ sheets/DNA-Sequencing-Costs-Data books/NBK91503/pdf/Bookshelf_NBK91503.pdf 12 “About one-in-five Americans use a smart watch or 3 K Bíró et al., “Creating a common language: defining fitness tracker,” January 2020, Pew Research Centre individualized, personalized and precision prevention web page, accessed 8 August 2020, https://www. in public health,” Journal of Public Health, 2018, pewresearch.org/fact-tank/2020/01/09/about-one-in- https://academic.oup.com/jpubhealth/article/40/4/ five-americans-use-a-smart-watch-or-fitness-tracker/ e552/4979516 13 “The 100,000 Genome Club,” Genetic Engineering & 4 Council conclusions on personalised medicine for Biotechnology News, 12 September 2018, https://www. patients, December 2015, Doc. no. 15054/15, http://data. genengnews.com/insights/the-100000-genomes-club/; consilium.europa.eu/doc/document/ST-15054-2015- “Playing with genes: The good, the bad and the ugly,” INIT/en/pdf UN Department of Economic and Social Affairs Frontier Technology Quarterly, 2019, https://www.un.org/ 5 National Institutes of Health, “What is precision development/desa/dpad/wp-content/uploads/sites/45/ medicine?” web page, accessed 6 August 2020, https:// publication/FTQ_May_2019.pdf ghr.nlm.nih.gov/primer/precisionmedicine/definition 14 European Commission, Benchmarking Deployment 6 These enablers have long roots in medicine. Indeed, of eHealth among General Practitioners (2018), amid the rapid innovation occurring in the field, it is 2018, https://www.ictandhealth.com/wp-content/ important to remember how much of today’s progress is uploads/2019/08/BenchmarkingDeploymentofe part of a longer evolution and reflects aims that clinicians HealthamongGeneralPractitioners2018.pdf have always shared. As Marc S. Williams, professor and director emeritus of the Geisinger Genomic Medicine 15 US Office of the National Coordinator of Health Institute, explains, “‘precision medicine’ is ‘medicine’.” Information Technology, “Health IT Dashboard,” web site, access 8 August 2020, https://dashboard.healthit.gov/ 7 For example, the works of ancient Greek medical apps/health-information-technology-data-summaries. writers such as Hippocrates and Galen are replete with php?state=National&cat9=all+data&cat1=ehr case studies drawn from interactions with patients. +adoption See: Trygve Nissen and Rolf Wynn, “The history of the case report: a selective review,” Journal of the Royal 16 For further discussion, see Amy Nordo et al., “Use of Society of Medicine Open, 2014, https://www.ncbi. EHRs data for clinical research: Historical progress and nlm.nih.gov/pmc/articles/PMC4012665/. Indeed, a recent current applications,” Learning Health Systems, 2019; analysis of a medieval medical pharmacopoeia, the Lylye Martin Cowie et al., “Electronic health records to facilitate of Medicynes, found that despite knowledge constraints, clinical research,” Clinical Research in Cardiology, 2016. doctors from the period took a rational approach to fashioning treatments, some of which were successful. 17 AVIESAN, Genomic Medicine France 2025, 2016, https:// See: “Data-mining medieval text reveals medically solidaritessante.gouv.fr/IMG/pdf/genomic_ bioactive ingredients,” MIT Technology Review, 1 August medicine_france_2025.pdf. 2018, https://www.technologyreview. com/2018/08/01/141220/data-mining-medieval-text- 18 Ewan Birney et al., “Genomics in healthcare: GA4GH reveals-medically-bioactive-ingredients/ looks to 2022,” bioRxiv, 2017, https://www.biorxiv.org/ content/10.1101/203554v1.full. 8 Nicholas Schork, “Personalized medicine: Time for one- 19 integrated person trials,” Nature, 2019. The 1,000 Genomes Project Consortium, “An map of genetic variation from 1,092 human

genomes,” Nature, https://www.ncbi.nlm.nih.gov/pmc/ initiatives-for-physicians/ articles/PMC3498066/?. 30 Economist Intelligence Unit calculations based on 20 Raag Agrawal and Sudhakaran Prabakaran, “Big data in Caron Molster et al., “Survey of healthcare experiences digital healthcare: lessons learnt and recommendations of Australian adults living with rare diseases,” Orphanet for general practice,” Heredity, 2020, https://www. Journal of Rare Diseases, 2016, https://www.ncbi.nlm. nature.com/articles/s41437-020-0303-2 nih.gov/pmc/articles/PMC4806449/pdf/13023_2016_ Article_409.pdf 21 Artificial intelligence for genomic medicine, 2020, https://www.phgfoundation.org/documents/artificial- 31 For an overview of the programme, see Gareth intelligence-for-genomic-medicine.pdf Baynam et al., “Initiating an undiagnosed diseases program in the Western Australian public health system,” 22 Jordi Remon and Rodrigo Dienstmann, “Precision Orphanet Journal of Rare Diseases, 2017, https://ojrd. oncology: separating the wheat from the chaff,” biomedcentral.com/track/pdf/10.1186/s13023-017- ESMO Open, 2018; John Marquart et al., “Estimation 0619-z, Georgia Hay and Florian Klonek, “Solving the of the Percentage of US Patients With Cancer Who Unsolvable: How De-Centralized Knowledge Sharing Benefit From Genome-Driven Oncology,” JAMA, 2018, Helps Diagnose Children With Rare Diseases,” Centre for https://jamanetwork.com/journals/jamaoncology/ Transformative Work Design blog, 2018, https://www. fullarticle/2678901 sketchingworkdesign.com/undiagnosed-diseases

23 Economist Intelligence Unit, Lung cancer in Latin 32 For details see Takeya Adachi et al., “Japan’s initiative on America: Time to stop looking away, 2018. rare and undiagnosed diseases (IRUD),” European Journal of Human Genetics, 2017, https://www.nature.com/ 24 Jordi Remon and Rodrigo Dienstmann, “Precision articles/ejhg2017106 oncology: separating the wheat from the chaff,” ESMO Open, 2018. 33 “Meeting to fast track progress on rare disease research,” Nanbyo Research from Japan (web site), 15 25 Economist Intelligence Unit analysis of data in March 2019, https://www.nanbyo-research.jp/feature/47/ Personalised Medicine Coalition, Personalized Medicine meeting-to-fast-track-progress-on-rare-disease- at FDA: A Progress Report & Outlook, [2019], research Personalized Medicine at FDA: The Scope & Significance of Progress in 2019, [2020]. 34 Takeya Adachi et al., “Survey on patients with undiagnosed diseases in Japan,” Orphanet Journal of 26 Fränce Hardtstock et al., “Real-world treatment and Rare Diseases, 2018, https://ojrd.biomedcentral.com/ survival of patients with advanced non-small cell lung articles/10.1186/s13023-018-0943-y Cancer: a German retrospective data analysis,” BMC Cancer, 2020, https://bmccancer.biomedcentral.com/ 35 Zornitza Stark et al., “Does genomic sequencing early in articles/10.1186/s12885-020-06738-z the diagnostic trajectory make a difference? A follow- up study of clinical outcomes and cost-effectiveness,” 27 Economist Intelligence Unit, Suffering in Silence: Genetics in Medicine, 2019, https://pubmed.ncbi.nlm.nih. Assessing Rare Disease Awareness and Management in gov/29765138/ Asia-Pacific, 2020, https://eiuperspectives.economist. com/sites/default/files/eiu_suffering_in_silence_rare_ 36 Takeya Adachi et al, “Strategic Outlook toward 2030: diseases_apac_report_0.pdf Japan’s research for allergy and immunology – Secondary Publication,” Allergology International, 2020, https:// 28 Economist Intelligence Unit analysis of data in www.researchgate.net/publication/342498989_ Personalised Medicine Coalition, Personalized Medicine Strategic_Outlook_toward_2030_Japan%27s_research_ at FDA: A Progress Report & Outlook, [2019], for_allergy_and_immunology_-_Secondary_publication Personalized Medicine at FDA: The Scope & Significance of Progress in 2019, [2020]. 37 Lisa Brown et al., “Economic Utility: Combinatorial Pharmacogenomics and Medication Cost Savings for 29 Patti Engel et al., “Physician and Patient Perceptions Mental Health Care in a Primary Care Setting,” Clinical Regarding Physician Training in Rare Diseases,” Journal Therapeutics, 2017, https://www.clinicaltherapeutics. of Rare Disorders, 2013, https://www.engagehealth. com/article/S0149-2918(17)30060-7/pdf com/current-issues/insights-publications/physician- and-patient-perceptions-regarding-physician-training- 38 Essra Youssef et al. “Pharmacogenomic testing and its in-rare-diseases-the-need-for-stronger-educational- future in community pharmacy,” The Pharmaceutical

Journal, 2020, https://www.pharmaceutical-journal.com/ accessed 8 September 2020 (percentage figure based on cpd-and-learning/learning-article/pharmacogenomic- Economist Intelligence Unit calculations). testing-and-its-future-in-community- pharmacy/20207342.article?firstPass=false 49 Amber Dance, “Coronavirus vaccines get a biotech boost: Advances in technology are accelerating the 39 Keira Cohen, “Deciphering drug resistance in search for drugs to arm the immune system against Mycobacterium tuberculosis using whole-genome SARS-CoV-2,” Nature, 2020, https://www.nature.com/ sequencing: progress, promise, and challenges,” Genetic articles/d41586-020-02154-2 Medicine, 2019. 50 Nathan Grubaugh et al., “Making Sense of Mutation: 40 Jasmine Lee et al., “Qualifying and quantifying What D614G Means for the COVID-19 Pandemic the precision medicine rhetoric,” BMC Genomics, Remains Unclear,” Cell, 2020, https://www.cell.com/ 2019, https://bmcgenomics.biomedcentral.com/ cell/pdf/S0092-8674(20)30817-5.pdf; Ewen Callaway, articles/10.1186/s12864-019-6242-8 “The coronavirus is mutating – does it matter?”, Nature, 8 September 2020, https://www.nature.com/articles/ 41 Tatiane Yanes et al., “Clinical applications of polygenic d41586-020-02544-6 breast cancer risk: a critical review and perspectives of an emerging field,” Breast Cancer Research, 2020, 51 Bas Oude Munnink et al., “Rapid SARS-CoV-2 whole- https://breast-cancer-research.biomedcentral.com/ genome sequencing and analysis for informed public articles/10.1186/s13058-020-01260-3 health decision-making in the Netherlands,” Nature Medicine, 2020, https://www.nature.com/articles/ 42 Updated data communicated by Marc Williams. For s41591-020-0997-y details of how the programme works, see Marc Williams et al., “Patient-Centered Precision Health in a Learning 52 Sarah Nadeau, “The origin and early spread of SARS- Health Care System: Geisinger’s Genomic Medicine CoV-2 in Europe,” MedRxiv, 2020, https://www.medrxiv. Experience,” Health Affairs, 2018, https://pubmed.ncbi. org/content/10.1101/2020.06.10.20127738v1 nlm.nih.gov/29733722/ 53 Xueyan Mei et al., “Artificial intelligence–enabled rapid 43 Victor Dzau et al., “Aligning incentives to fulfill the diagnosis of patients with COVID-19,” Nature Medicine, promise of Personalized Medicine,” Lancet, 2015, https:// 2020, https://www.nature.com/articles/ www.thelancet.com/journals/lancet/article/PIIS0140- s41591-020-0931-3; Shuai Wang et al. “A deep learning 6736(15)60722-X/fulltext algorithm using CT images to screen for Corona Virus Disease 44 Miriam Kasztura et al., “Cost-effectiveness of (COVID-19),” MedRxiv, 2020, https://www.medrxiv.org/ precision medicine: a scoping review,” International content/10.1101/2020.02.14.20023028v5.full.pdf Journal of Public Health, 2019, https://link.springer.com/ article/10.1007/s00038-019-01298-x#Tab2 54 Sonja Rasmussen, “Precision Public Health as a Key Tool in the COVID-19 Response,” JAMA, 2020, https:// 45 World Health Organisation, “Public Health,” Health jamanetwork.com/journals/jama/fullarticle/2769563 Systems Strengthening Glossary web site accessed 28 August 2020, https://www.who.int/healthsystems/ 55 Roberto Gatti et al., “Machine learning reveals that hss_glossary/en/index8.html prolonged exposure to air pollution is associated with SARS-CoV-2 mortality and infectivity in Italy,” 46 Both authors were supportive of precision public Environmental Pollution, 2020, https://pubmed.ncbi.nlm. health. See: Shawn Dolley, “Big Data’s Role in Precision nih.gov/32882464/; Marco Mele and Cosimo Magazzino, Public Health,” Frontiers in Public Health, 2018, https:// “Pollution, economic growth, and COVID-19 deaths www.frontiersin.org/articles/10.3389/fpubh.2018.00068/ in India: a machine learning evidence,” Environmental full; Tarun Weeramanthri et al., “Editorial: Precision Public Science and Pollution Research International, 2020, Health,” Frontiers in Public Health, 2018, https://www. https://pubmed.ncbi.nlm.nih.gov/32886309/ frontiersin.org/articles/10.3389/fpubh.2018.00121/full; 56 For a taste of the research, see review article Madalina 47 Jason Ladner, “Precision epidemiology for infectious Elena Carter-Timofte et al., “Deciphering the Role of Host disease control,” Nature Medicine, 2019, http:// Genetics in Susceptibility to Severe COVID-19,” Frontiers evolve.zoo.ox.ac.uk/Evolve/Oliver_Pybus_files/ in Immunology, 2020, https://www.frontiersin.org/ PrecisionEpidemiologyForInfectiousDiseaseControl.pdf articles/10.3389/fimmu.2020.01606/full; Maria Smatti et al., “Host Genetic Variants Potentially Associated With 48 https://phgkb.cdc.gov/PHGKB/coVInfoStartPage.action SARS-CoV-2: A Multi-Population Analysis,” Frontiers in Genetics, 2020, https://www.frontiersin.org/

articles/10.3389/fgene.2020.578523/full e030279.full.pdf.

57 Janie Shelton et al., “Trans-ethnic analysis reveals 65 The history of the term precision public health may genetic and non-genetic associations with COVID-19 explain some of this concern. When the term was susceptibility and severity,” MedRxiv, 2020, https://www. first used in Western Australia in 2013, it involved the medrxiv.org/content/10.1101/2020.09.04.20188318v1 provision of genetic sequencing to help diagnose many patients with rare diseases,66 straddling the grey area 58 Jianguo Xiao, “Variation in Population Vulnerability between individual medical care (diagnosis) and public to Heat Wave in Western Australia,” Frontiers in health (epidemiology). Similarly, the US CDC’s efforts Public Health, 2017, https://www.frontiersin.org/ in precision public health grew out of its work on public articles/10.3389/fpubh.2017.00064/full health genomics.67 Fears about a focus on genomics and AI have been further exacerbated by public figures 59 Robert Reiner et al., “Variation in Childhood Diarrheal describing precision public health exclusively in such Morbidity and Mortality in Africa, 2000–2015,” terms. (For example, see the UK health minister’s NEJM, 2018, https://www.nejm.org/doi/full/10.1056/ comments when announcing a precision prevention NEJMoa1716766; Natalia Bhattacharjee et al., “Mapping initiative.)68 exclusive breastfeeding in Africa between 2000 and 2017,” Nature Medicine, 2019, https://www.nature.com/articles/ 66 For some of Khoury’s public comments, see Muin s41591-019-0525-0. Khoury et al, “Precision Public Health for the Era of Precision Medicine,” American Journal of Preventative 60 “World first as UK aid brings together experts to predict Medicine, 2016, https://www.ncbi.nlm.nih.gov/pmc/ where cholera will strike next,” DfID Press release, 28 articles/PMC4915347/; Muin Khoury et al, “Beyond Public August 2018; “How Met Office weather data is being used Health Genomics: Can Big Data and Predictive Analytics to predict cholera outbreaks,” Daily Telegraph, 29 August Deliver Precision Public Health?”, 2018, https://pubmed. 2018. ncbi.nlm.nih.gov/31315115/; Muin Khoury, “Precision Public Health: What Is It?”, blog post, 15 May 2018, 61 UK Department of Health and Social Care, “Prevention https://blogs.cdc.gov/genomics/2018/05/15/precision- is better than cure – Matt Hancock’s speech to public-health-2/ International Association of National Public Health Institutes,” 5 November 2018, https://www.gov.uk/ 67 The editors of which were mostly from the Western government/speeches/prevention-is-better-than-cure- Australian group involved in introducing genomic matt-hancocks-speech-to-ianphi sequencing to screen for rare disease.

62 David Lazer and Ryan Kennedy, “What We Can Learn 68 Tarun Weeramanthri et al., “Editorial: Precision Public From the Epic Failure of Google Flu Trends,” Wired, 18 Health,” Frontiers in Public Health, 2018, https://www. January 2015, https://www.wired.com/2015/10/can- frontiersin.org/articles/10.3389/fpubh.2018.00121/full; learn-epic-failure-google-flu-trends/ 69 Clayton Christensen, Richard Bohmer and John Kenagy, 63 Adam Buchanan et al., “Clinical outcomes of a genomic “Will disruptive innovations cure healthcare?” Harvard screening program for actionable genetic conditions,” Business Review, September-October 2000. Genetics in Medicine, 2020, https://www.nature.com/ 70 articles/s41436-020-0876-4 Center for Connected Medicine and KLAS, Top of Mind for Top Health Systems 2020, 2020. 64 For a more detailed discussion of this viewpoint, see: David Taylor-Robinson and Frank Kee, “Precision public 71 See also, M. Walid Qoronfleh, “Health is a political health – the Emperor’s new clothes,” International Journal choice: why conduct healthcare research? Value, of Epidemiology, 2019, https://academic.oup. com/ije/ importance and outcomes to policy makers,” Life, article/48/1/1/5096004; Frank Kee and David Taylor- Sciences, Society and Policy, 2020, https://lsspjournal. Robinson, “Scientific challenges for precision public biomedcentral.com/articles/10.1186/s40504-020- health,” Journal of Epidemiology and Community Health, 00100-8 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC7079187/; Merlin Chowkwanyun, “Precision” Public 72 For a light-hearted but useful distillation of Health – Between Novelty and Hype,” NEJM, 2018, change management best practice, see John https://www.nejm.org/doi/full/10.1056/NEJMp1806634; Kotter and Holger Rathgeber, Our Iceberg is Dana Olstad and Lynn McIntyre, Melting: Changing and Succeeding Under and “Reconceptualising precision public health,” BMJ Open, Conditions, 2005, https://pdfs.semanticscholar. 2019, https://bmjopen.bmj.com/content/bmjopen/9/9/ org/2810/40cf99b29063fa0b121132a1382b5273c058.pdf

73 Laurenz Govaerts et al., “Shedding Light on in breast cancer—an European consensus statement and Reimbursement Policies of Companion Diagnostics expert recommendations,” European Journal of Cancer, in European Countries,” Value in Health, 2020, 2019, https://www.sciencedirect.com/science/article/pii/ https://www.sciencedirect.com/science/article/pii/ S0959804918314357 S1098301520300899 84 Diane Hauser et al., “Views Of Primary Care Providers 74 Economist Intelligence Unit, The digitisation of On Testing Patients For Genetic Risks For Common the German health system and value-based care: Chronic Diseases,” Health Affairs, 2018, https://www. Opportunities and limitations, forthcoming. healthaffairs.org/doi/abs/10.1377/hlthaff.2017.1548; Susanne Haga et al., “Primary Care Physicians’ 75 Devender Dhanda et al., “Payer Preferences and Knowledge, Attitudes, and Experience with Personal Willingness to Pay for Genomic Precision Medicine: A Genetic Testing,” Journal of Personalized Medicine, 2019, Discrete Choice Experiment,” Journal of Managed Care https://www.mdpi.com/2075-4426/9/2/29/htm; CV and Speciality Pharmacy, 2020, https://pubmed.ncbi.nlm. Chambers et al., “Primary Care Physicians’ Experience nih.gov/32223606/ and Confidence with Genetic Testing and Perceived Barriers to Genomic Medicine,” Journal of Family 76 Center for Connected Medicine and KLAS, Top of Mind Medicine, 2015, https://austinpublishinggroup.com/ for Top Health Systems 2020, 2020, family-medicine/fulltext/jfm-v2-id1024.php.

77 Eric Faulkner et al., “Being Precise About Precision 85 Robin Bennett et al., “Medical genetics and genomics Medicine: What Should Value Frameworks Incorporate education: how do we define success? Where do we to Address Precision Medicine?”, Value in Health, 2020, focus our resources?”, Genetics in Medicine, 2017, https:// https://www.valueinhealthjournal.com/article/S1098- www.nature.com/articles/gim201777 3015(20)30092-9/fulltext#%20 86 Milena Paneque et al., “A systematic review of 78 For a detailed discussion, see James Love-Koh et al., interventions to provide genetics education for primary “The Future of Precision Medicine: Potential Impacts for care,” BMC Family Practice, 2016, https://bmcfampract. Health Technology Assessment,” Pharmacoeconomics, biomedcentral.com/articles/10.1186/s12875-016-0483- 2018, https://www.ncbi.nlm.nih.gov/pmc/articles/ 2; Divya Talwar et al., “Genetics/genomics education for PMC6244622/; Eric Faulkner et al., “Being Precise About nongenetic health professionals: a systematic literature Precision Medicine: What Should Value Frameworks review,” Genetics in Medicine, 2016, https://www.nature. Incorporate to Address Precision Medicine?”, Value in com/articles/gim2016156 Health, 2020, https://www.valueinhealthjournal.com/ article/S1098-3015(20)30092-9/fulltext#%20 87 Muin Khoury and George Mensah, “Predictive Analytics, Implementation Science, Precision Medicine 79 Eric Faulkner et al., “Being Precise About Precision and Precision Public Health,” CDC blog post, July 28, Medicine: What Should Value Frameworks Incorporate 2020, https://blogs.cdc.gov/genomics/2020/07/28/ to Address Precision Medicine?”, Value in Health, 2020, predictive-analytics/ https://www.valueinhealthjournal.com/article/S1098- 3015(20)30092-9/fulltext#%20 88 Katie Snape et al., “The new genomic medicine service and implications for patients,” Clinical Medicine, 80 Deborah Maiese et al., “Current conditions in medical 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/ genetics practice,” Genetics in Medicine, 2019, https:// PMC6752257/pdf/clinmed-19-4-273.pdf www.nature.com/articles/s41436-018-0417-6 89 Jillian Oderkirk, “Readiness of electronic health record 81 MaryAnn Abacan et al., “The Global State of the Genetic systems to contribute to national health information Counseling Profession,” European Journal of Human and research,” OECD Health Working Papers, no. Genetics, 2019, https://www.nature.com/articles/s41431- 99, November 2017, https://www.oecd-ilibrary.org/ 018-0252-x#Tab2 docserver/9e296bf3-en.pdf?

82 US National Society of Genetic Counselors, “Genetic 90 Trishan Panch et al., “The ‘inconvenient truth’ about AI Counselor Workforce Initiatives,” web page accessed 3 in healthcare,” NPJ Digital Medicine, 2019, https://www. September 2020, https://www.nsgc.org/page/genetic- nature.com/articles/s41746-019-0155-4; Jillian Oderkirk, counselor-workforce-initiatives-532 “Readiness of electronic health record systems to contribute to national health information and research,” 83 Christian Singer et al., “Genetic counselling and testing OECD Health Working Papers, no. 99, November 2017, of susceptibility genes for therapeutic decision-making https://www.oecd-ilibrary.org/docserver/9e296bf3-en.

pdf?expires=1599152348&id=id&accname=guest& service and implications for patients,” Clinical Medicine, checksum=2CA55EF7E97BDAB1E6644F93C87871EA; 2019, https://www.ncbi.nlm.nih.gov/pmc/articles/ Alvin Rajkoma et al., “Machine Learning in Medicine,” PMC6752257/pdf/clinmed-19-4-273.pdf NEJM, 2019, https://www.nejm.org/doi/full/10.1056/ 102 NEJMra1814259. https://www.england.nhs.uk/publication/genomics- testing-reporting-specification-v1-0-for-2020-21/ 91 George Simon et al, “Applying Artificial Intelligence to Address the Knowledge Gaps in Cancer Care,” The 103 European Medicines Agency, EMA Regulatory Science Oncologist, 2019, https://www.ncbi.nlm.nih.gov/pmc/ to 2025: Strategic reflection, 2020, https://www.ema. articles/PMC6656515/pdf/onco12748.pdf europa.eu/en/documents/regulatory-procedural- guideline/ema-regulatory-science-2025-strategic- 92 Economist Intelligence Unit, Risks and Rewards: reflection_en.pdf Scenarios around the economic impact of machine learning, 2018, http://eiuperspectives-stage.economist 104 WEF, Precision Medicine Vision Statement, 2020, .com/sites/default/files/Risks_and_rewards_2018.2.7.pdf http://www3.weforum.org/docs/WEF_Global_Precision_ Medicine_Council_Vision_Statement_2020.pdf 93 “Editorial: A milestone in human genetics highlights diversity gaps,” Nature, 27 May 2020, 105 Sara Gerke et al., “The need for a system view to https://www.nature.com/articles/d41586-020-01551-x regulate artificial intelligence/ machine learning-based software as medical device,” NPJ Digital Medicine, 2020, 94 Trishan Panch et al., “The ‘inconvenient truth’ about AI https://www.nature.com/articles/s41746-020-0262-2; I in healthcare,” NPJ Digital Medicine, 2019, Glenn Cohen et al., “The European artificial intelligence https://www.nature.com/articles/s41746-019-0155-4. strategy: implications and challenges for digital health,” The Lancet Digital Health, 2020, https://www.thelancet. 95 Peter Keeling et al., “Challenges in the clinical com/journals/landig/article/PIIS2589-7500(20)30112-6/ implementation of precision medicine companion fulltext; Michael Cleary, “Artificial Intelligence: The Key diagnostics,” Expert Review of Molecular Diagnostics, to Unlocking Novel Real-World Data?”, ISPOR Values 2020, https://www.tandfonline.com/doi/full/10.1080/147 and Outlook Spotlight, March/April 2019, https://www. 37159.2020.1757436 ispor.org/docs/default-source/publications/value- outcomes-spotlight/march-april-2019/vos-feature. 96 “Addressing the critical lack of skilled lab workers,” pdf?sfvrsn=e3703821_0 Healthcare in Europe, 20 February 2020 https:// healthcare-in-europe.com/en/news/addressing-the- 106 Economist Intelligence Unit, Creating Healthy critical-lack-of-skilled-lab-workers.html; “Solving the Partnerships: The Role of Patient Value and Patient- Clinical Laboratory Workforce Shortage,” Clinical Lab centred Care in Health Systems, 2019, https:// Manager, 6 July 2020, https://www.clinicallabmanager. patientcentredcare.eiu.com/whitepaper.pdf com/trends/laboratory-staffing/solving-the-clinical- laboratory-workforce-shortage-23189 107 Economist Intelligence Unit, Creating Healthy Partnerships: The Role of Patient Value and Patient- 97 Peter Keeling et al., “Challenges in the clinical centred Care in Health Systems, 2019, https:// implementation of precision medicine companion patientcentredcare.eiu.com/whitepaper.pdf; Economist diagnostics,” Expert Review of Molecular Diagnostics, Intelligence Unit, State of patient centricity 2020: 2020, https://www.tandfonline.com/doi/full/10.1080/147 Advancing from patient-first intentions to true co- 37159.2020.1757436 creation, 2020, https://eiuperspectives.economist.com/ sites/default/files/eiu_-_medidata_-_state_of_patient_ 98 Sally Davies, Annual Report of the Chief Medical centricity_2020_0.pdf Officer 2016, Generation Genome, 2017, https://assets. publishing.service.gov.uk/government/uploads/system/ 108 For a discussion of such confusion, see Jane Wilcock, uploads/attachment_data/file/631043/CMO_annual_ “Personalised and precision medicine – definitions and report_generation_genome.pdf distinctions,” BMJ, 2019, https://blogs.bmj.com/bmj/2019 /09/06/jane-wilcock-personalised-and-precision- 99 Ibid. medicine-definitions-and-distinctions/

100 https://www.england.nhs.uk/publication/national- 109 For detailed discussion of Patient Generated Health genomic-test-directories/ Data, see: Peter West et al. “Common Barriers to the Use of Patient-Generated Data Across Clinical Settings,” 101 Katie Snape et al., “The new genomic medicine Proceedings of the 2018 CHI Conference on Human

Factors in Computing Systems, Paper No. 484, 2018; US Trials: Overcoming Critical Barriers,” Current Problems Office of the National Coordinator for Health Information in Cardiology, 2019, https://www.sciencedirect.com/ Technology, Conceptualizing a Data Infrastructure for science/article/pii/S0146280618301889?via%3Dihub the Capture, Use, and Sharing of Patient-Generated Health Data in Care Delivery and Research through 116 Ibid. 2024, 2018; AM Lai et al, “Present and Future Trends in Consumer Health Informatics and Patient-Generated 117 “Data Snapshots,” All of Us Research Hub web Health Data,” IMIA Yearbook of Medical Informatics, page, accessed 8 September 2020, https://www. 2017. researchallofus.org/data-snapshots/

110 Stella Stergiopolous et al., “Measuring the Impact of Patient Engagement and Patient Centricity in Clinical Research and Development,” Therapeutic Innovation & Regulatory Science, 2020, https://pubmed.ncbi.nlm. nih.gov/32008233/; Economist Intelligence Unit, The Innovation Imperative: The Future of Drug Development Part I: Research Methods and Findings, 2018. https:// druginnovation.eiu.com/wpcontent/uploads/2018/10/ Parexel-innovations-in-drug-development_V10.pdf

111 Carla van El et al., “Whole-genome sequencing in health care: Recommendations of the European Society of Human Genetics,” European Journal of Human Genetics, 2013, https://www.nature.com/articles/ ejhg201346; Sarah Kalia et al., “Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics,” Genetics in Medicine, 2016, https://www.nature.com/articles/gim2016190.

112 SM Modell et al., “When Genetics Meets Religion: What Scientists and Religious Leaders Can Learn from Each Other,” Public Health Genomics, 2019, https://pubmed. ncbi.nlm.nih.gov/31801151/

113 See, for example, Torsten Voigt et al., “Willingness to donate genomic and other medical data: results from Germany,” European Journal of Human Genetics, 2020, https://www.nature.com/articles/s41431-020-0611-2; Jihoon Kim et al, “Patient Perspectives About Decisions to Share Medical Data and Biospecimens for Research,” JAMA Open Network, 2019, https://jamanetwork.com/ journals/jamanetworkopen/fullarticle/2748592; Emily Seltzer et al., “Patients’ willingness to share digital health and non-health data for research: a cross-sectional study,” BMC Medical Informatics and Decision Making, 2019, https://bmcmedinformdecismak.biomedcentral. com/articles/10.1186/s12911-019-0886-9.

114 Caroline Chen and Riley Wong, “Black patients miss out on promising cancer drugs,” ProPublica 19 September 2018; Vishal Bhatnagar et al., “FDA Analysis of Racial Demographics in Multiple Myeloma Trials,” Blood, 2017.

115 Luther Clark et al., “Increasing Diversity in Clinical

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