Imaging in Preventive Medicine- Individualized Prevention & Early Interventions: A White Paper of the National Preventive Radiology Committee of Indian Radiological Imaging Association (IRIA)

Prepared By Dr Rijo Mathew Choorakuttil for the IRIA Preventive Radiology Committee

1. Dr Rijo Mathew Choorakuttil-National Co-ordinator
2. Dr Chander Lulla-Member
3. Dr Zubair Kazi- Member
4. Dr Umamaheswar Reddy-Member
5. Dr Ruchi Rastogi- Member
6. Dr Ramesh Shenoy- Member
7. Dr Rakesh Jamkhandikar-Member
8. Dr Ghanshyam Adhesharna- Member
9. Dr Devanand B-Member

Introduction

Medical imaging offers the possibility of minimal contact, non-invasive and painless identification of diseases at various stages. Imaging studies allow healthcare practitioners to objectively assess the onset and progress of disease and the effectiveness of interventions in a painless manner. Rapid advancements in medical imaging modalities have resulted in the evolution of techniques for better visualization of structures, in the reduction of turnaround times using better algorithms that provide better interpretations, and improved access through portable and point of care applications.

Screening is an important strategy in the identification of diseases in populations, Screening builds on the principle that early identification and management can mitigate short- and long-term effects of the disease state and often lead to decreased costs of treatment. [1,2] Screening programs are based on the magnitude and distribution of the disease at a national or regional level, the risk factors associated with the condition, the possibility and effectiveness of interventions, and evidence on the effectiveness of the screening protocols. Medical imaging is an integral part of screening and management of several public health conditions including tuberculosis, breast cancers, lung and colon cancers, coronary heart diseases, aneurysms, and congenital malformations in foetuses. These approaches play an important role in early identification, therapeutics, and assessment of the progress of disease and effectiveness of the interventions.

Individualized medicine offers the possibility of integrating population or healthcare setting-based screening approaches with personalized care at an individual level. Clinicians informally practise individualized medicine routinely as they integrate personal, family, environmental factors into the therapeutic care for each person. The medical model of individualized medicine emphasizes the customization of healthcare, with all decisions and practices tailored to individual patients in whatever ways possible and optimize compliance of the patient to the prescribed management strategy. The advances in medical imaging and their integration with screening protocols allow the possibility for early identification of biologic changes, or pathophysiologic changes, at a structural or functional level, even before symptoms of the condition manifest.

The sequencing of the human genome opened the possibility of genetic variants that may predispose to a disease, impact the progress or severity of the disease or regulate that person’s response to a given treatment.[3]. Proteomics and genomics have significant roles to play in monogenic diseases but impact more on the determination of predisposition to a condition and therapeutic responses in non-monogenic conditions and must be considered in the context of external variations that include environment, diet, exercise, and social circumstance. [3,4]. The main aspect of individualized medicine is the identification of early biomarkers that characterise a cellular or functional alteration and lead to subclinical or manifest disease status and its specific reaction to various therapeutic strategies. [5] Persons are now stratified into smaller subgroups related to their risk or potential treatment profiles characterised by a combination of genetic, biochemical, and imaging biomarkers which can be refined down to an individual level. [5]

Medical Imaging in Individualized Medicine

Medical imaging has an important role to play in three aspects of individualized medicine.

• The disease-prevention model
• The individualized diagnostic model
• The individualized therapeutic model

The disease-prevention model aims to identify early pre-clinical stages of disease and subgroups of patients at risk of developing symptoms and signs of abnormal structure and function. It relies on a combination of genetic, environmental, social and other information integrated with predictive biomarkers (biomolecular or imaging) that help to monitor disease development and preventive interventions. 

The Individualized diagnostics model aims to identify the specific molecular substrate, structural and functional basis of alterations leading to disease. These look carefully to identify the location and extent of primary and secondary changes integrating the physiological characteristics of disease lesions like perfusion, flow, metabolism, and diffusion.

The Individualized treatment model focuses on the identification of patient subgroups that are more likely to respond favourably to different therapeutic models integrating information on side effects or consequences, therapeutic modulations, and localized therapy. [6]

Medical imaging in clinical medicine is not restricted to the diagnosis of an abnormality- a disease, an injury, or a malformation but considers the localization of the abnormality, the extent of the abnormality and its impact on structural and functional parameters.

Medical Imaging can help to

• Assess physiology, organ function, biochemistry, metabolism, molecular biology, and functional genomics, proteomics, lipidomics, metabolomics, and epigenomics,
• Integrate information to predict the onset of disease,
• Localize the disease,
• Identify the spread of the disease to adjacent or distant tissues, organs, and structures,
• Assess the physiological environment and conditions of disease,
• Plan and guide surgical or minimally invasive surgery,
• Assess perfusion of lesions and diffusion in tissue and the vulnerability of adjacent organs to predict the success of interventions.

The variability of disease onset, progression and response to treatment within populations is increasingly recognized. Medical imaging provides the possibility of addressing these variations without relying entirely on ex-vivo or in-vitro testing. Medical imaging has the potential to guide the entire therapeutic planning by integrating quantitative imaging and volumetric assessments. These advantages include, but are not limited to the following:

• Early diagnosis of disease processes, even at a pre-clinical stage, through the visualisation of cellular and molecular processes using molecular imaging, can build to screening and clinical algorithms and early intervention.
• Identification of predictive imaging biomarkers that help clinicians and health care practitioners to stratify patient subgroups at risk of developing disease and monitoring of preventive measures.
• Identification of localised pathophysiology including metabolism, diffusion, and perfusion  of diseased tissue.
• Theranostics combines targeted imaging, diagnosis and targeted therapy and enables the identification of heterogeneous and localised response to therapy, radiogenomics, and image-guided interventions.
• Monitoring response to treatment and early identification of treatment responders and non-responders, identification of side effects and cost-effective therapies.
• Individualised, image-guided drug delivery systems and better drug development systems.

Common Terminologies to consider in Preventive, Personalized Medicine

Personalised Medicine

The US National Human Genome Research Institute defines personalised medicine as “an emerging practice of medicine that uses an individual’s genetic profile to guide decisions made regarding the prevention, diagnosis and treatment of disease. Knowledge of a patient’s genetic profile can help doctors select the proper medication or therapy and administer it using the proper dose or regimen”. [7]

The US National Cancer Institute describes personalised or precision medicine as “a form of medicine that uses information about a person’s genes, proteins, and environment to prevent, diagnose, and treat disease” [8]. Personalised medicine is uses specific information regarding a tumour to help diagnose, plan treatment, find out how well treatment is working, or make a prognosis in persons with cancer. [8]

The European Science Foundation describes personalised medicine as “a customisation of healthcare that accommodates individual differences as far as possible at all stages in the process, from prevention, through diagnosis and treatment, to post-treatment follow-up”. [9]

Pharmacogenomics

The study of how the genes of a person affect the way they respond to drugs.

Genomics

The use of genetic information to improve health outcomes.

Radiogenomics

Radiogenomics describes the relationship between imaging features of a lesion and the underlying genetic/molecular features and is helpful for improved personalised diagnosis, prognosis, and assessment of treatment response [10]

Theranostics

Theranostics is defined as ongoing efforts in clinical medicine to develop more specific, individualised therapies for various diseases and to combine diagnostic and therapeutic capabilities into a single agent.[11] 

Stratified Medicine

The identification of subgroups of patients with a particular disease who respond to a particular drug or are at risk of side effects in response to a certain treatment.

Disease Prevention

Current developments in image data acquisition and analysis enable the use of medical imaging to investigate specific pathophysiological stages of disease in a pre-symptomatic phase and at the population level. Population imaging is the large-scale application and analysis of medical images in controlled population cohorts or through specific screening programs. Population imaging can find biomarkers that predict later development of disease, either on their own or by supplementing established risk factors and can enable the stratification of a healthy population into different risk categories with a low, intermediate, and high risk of developing the disease. Each group might have its treatment regime, ranging from discharge, regular follow-up at several years, watchful waiting with an imaging follow-up after several months, or medical or surgical intervention. Imaging may become the key to identify people that could benefit from preventive intervention. Well-organized population screening protocols that use imaging biomarkers of disease states, targeted prevention of common human pathologies, optimal treatment planning and individualized therapy can result in substantial improvement of the quality of life. This approach also offers the advantage of healthcare delivery at possibly lower costs to the population at large and address social and ethical issues related to access to and affordability of health care.

Cardiac disease is a good example of individualized prevention. Individuals are characterized as low, intermediate, and high risk based on the classical risk factors and high-risk individuals are treated with intensive medical treatment while low-risk individuals are helped with lifestyle modifications.  Candidate imaging biomarkers are the CT-derived calcium score from the coronary arteries or more peripherally located arteries, US-derived intima-media thickness, US- or MRI-derived pulse wave velocity, or MRI-based plaque composition. [12-14] These imaging biomarkers can predict later development of disease, either on their own or by supplementing established risk factors. 

Fetal Doppler studies in the prevention of preterm pre-eclampsia is another example of the role of medical imaging in preventive medicine. First-trimester fetal Doppler studies integrated with clinical, personal, and family history, and mean arterial pressures help to identify women at risk for the development of pre-term pre-eclampsia during pregnancy. Early initiation of low dose aspirin 150mg at bedtime helps to minimize the risk of preterm preeclampsia.[15]

The possibility of overdiagnosis in screening and individualized medicine exists when an asymptomatic disease is diagnosed (either by screening or as an incidental finding). Overdiagnosis is the diagnosis of irrelevant diseases, diseases that are so stable or indolent that they would not have become clinically relevant during the subject’s life. Overdiagnosis can lead to unneeded treatment with potentially harmful side effects and cause an economic and emotional burden. The challenge for preventive radiology is to recognise when the burdens of treatment outweigh the benefits for a given patient, after balancing the individual characteristics of the subject, their values and preferences, and family and societal environment.

Individualized diagnosis

The classical diagnostic paradigm involves a constellation of clinical findings, integrated with laboratory findings and imaging findings. Imaging has conventionally helped to identify the location and extent of a structural abnormality and has grown to identify functional changes at the molecular levels as well. Recent advances in imaging using specific radiotracers provide additional tools for better characterisation of a lesion at the molecular level. Combining information from different functional and molecular parameters extracted from multimodality imaging techniques can reduce the need for histopathological diagnosis of lesions.

Individualized diagnostic procedures

Medical imaging is by default, geared towards providing the right imaging modality at the right quality and with minimal side effects or appropriate safety. The concept of individualized diagnostic procedures is therefore not new to Radiology. Specific imaging protocols per modality are available for a broad range of clinical problems. These protocols differ in the effective patient dose, the amount of contrast injected, injection rate, delay times, image reconstruction algorithms, contrast weightings, slice thicknesses and image orientation among other parameters and are not a one shoe size fits approach. Examples of tailored protocols include low-dose CT protocols for urinary stone detection, CT angiography for detection of arterial stenosis and MRI for spinal cord diseases, optimisation of a diagnostic procedure based on patient characteristics like the use of patient weights to determine contrast media dosing, avoiding the use of ionising radiation in children and pregnant women, to prevent the use of IV contrast media based on eGFR levels, and automated tube voltage selection and tube current modulation in CT based on measured attenuation.

Imaging and the selection of therapy

Improved staging of the disease using medical imaging may avoid unnecessary surgical interventions, which increases the morbidity of disease without a substantial benefit in the reduction of mortality. [16,17] Consensus criteria and guidelines have been established based on large clinical studies combining multi-modality imaging criteria. Specific examples in the management of the disease based on its extent identified through imaging are available in the oncology, cardiovascular, cerebrovascular disciplines amongst others. These include, but are not limited to,

• The decision to treat unruptured intracranial aneurysms based on the location and maximum diameter of the aneurysm,
• Larger abdominal aneurysms greater than 5.5 cm in size are treated while smaller aneurysms are monitored during follow-up,
• Replacement of catheter angiography with ultrasound, CT and MR angiography.
• Tissue Biopsies and Imaging
• US-, CT- or MRI-guided biopsy sampling is often the least invasive method to obtain relevant material for the in vitro diagnosis of disease and determine the progress of the disease.

Specific examples [18-22] include:

• The use of MRI-guided or contrast-enhanced transrectal US-guided biopsy of the prostate is useful to detect prostate cancer in patients with prior negative biopsy results.
• US- and MRI-guided percutaneous breast biopsy, which has replaced surgical biopsy as the initial method of diagnosis for most breast lesions.
• US-guided core biopsy of suspicious axillary lymph nodes in patients with breast cancer allows for the identification of metastatic nodes preoperatively.
• CT-guided bone biopsy in patients with suspected bone metastasis supports a final diagnosis.
• US-guided biopsy in sub-centimetre neck lymph nodes improves tumour staging in head and neck cancer. 

Prognostic and Predictive biomarkers

Medical imaging provides two different types of biomarkers that are of particular importance- prognostic and predictive biomarkers. Prognostic imaging biomarkers predict the likelihood of disease progression in the absence of treatment considerations and are valuable to identify aggressive disease that requires immediate treatment and indolent disease that can safely be left alone. Predictive biomarkers can help to indicate the response to drug treatment or the success of treatment by surgery, interventional radiology or radiotherapy. Both types of biomarkers are relevant as they influence the decision for the type, length, and intensity of treatment. 

Molecular Imaging

Molecular imaging can provide important information about physiology, metabolism, molecular biological processes, and functional genomics. Multiple methods are described for imaging the temporal and spatial biodistribution of a molecular probe as well as related biological processes such as cell proliferation, apoptosis, angiogenesis, hypoxia, and gene activation and expression. These new methods measure and quantify biological processes and also localise the measured entities onto a high-resolution anatomical and functional image. Theranostics allow for improved staging of the tumour, for imaging of the biodistribution of the target to predict the biodistribution of the radiation dose and to individually monitor the efficacy of treatment.

Radiogenomics

Radiogenomics is a new approach in which large sets of complex descriptors of disease are extracted from routine clinical images and related to molecular biology and gene expression patterns of disease. It is presumed that the observed image is the product of mechanisms occurring at a genetic and molecular level. Thus, parameters extracted through image processing and analysis are linked to the genotypic and phenotypic characteristics of the tissue. Medical images inherently contain a wealth of mineable information, which reflects genetic and molecular information of disease in an individual patient, which allows imaging phenotypes to serve as surrogates for the unique molecular programmes that typify a molecular subtype of cancer. Radiogenomics can help patient management and improve existing staging and diagnostic schemes. Imaging can determine the molecular diversity of disease and thereby stratify patients into molecular subclasses with different prognoses.

Evaluating Treatment Responses

Imaging plays an important role in the assessment of therapeutic response. Decreased morbidity and mortality have been endpoints for treatment evaluation. Medical imaging can provide more objective measures of treatment response in most disease compared to monitoring symptoms. An early and accurate therapeutic response evaluation can influence the decision on discontinuation of treatment, treatment adjustment and/or additional treatment. Imaging can prevent prolonged exposure to ineffective treatments and allow early change to alternative therapies. Imaging not only plays a role in assessing response to chemotherapy, radiotherapy and/or targeted therapies but also in the monitoring of changes after image-guided intervention.

Further Considerations

Imaging procedures are based on the clinical problem and patient characteristics. Screening for preclinical disease can be done with imaging. Imaging biomarkers can help stratify individuals for preventive intervention. Treatment decisions can be based on the in vivo visualisation of the location and extent of an abnormality as well as the loco-regional physiological, biochemical, and biological processes using structural and molecular imaging. Image-guided biopsy provides tissue specimens for relevant and focused genetic/molecular characterisation. Besides, radiogenomics relate imaging biomarkers to these genetic and molecular features. Imaging can guide patient-tailored therapy planning, therapy monitoring and follow-up of disease, as well as targeting non-invasive or minimally invasive treatments, especially with the rise of theranostics. Radiologists must be prepared for this new paradigm as it will mean changes in training, clinical practice and research.

Radiologists must be actively involved in

• Promotion of the use of non-invasive medical imaging as part of preventive Radiology and Individualized medicine.
• Integration of anatomical, functional and molecular imaging through the radiodiagnosis department.
• Validation of quantitative imaging biomarkers for diagnosis and treatment response assessment for various public health conditions pertinent to India and based on the prevalence of these conditions in India
• Implementation of image-guided interventional procedures for providing the most accurate tissue samples for pathology-based biomarkers.
• Integration of personalised diagnostic imaging and therapeutic procedures (theranostics).
• Provision of personalised image-based phenotypic results that complement genomic analysis (radiogenomics).
• Establishment of large imaging biobanks in India that collate multicenter data at a regional and national level.
• Delivery of personalised treatment via a wide range of interventional radiologic procedures.

Road Ahead

Radiologist in India must consider several major changes in their practice as part of the continuous development of their discipline.

• A paradigm shift in the attitude of Radiologists from “report based on request” to a proactive “identification of abnormality” genre.
• Skill upgradation and training in the widespread use of imaging biomarkers
• Research in the identification and evaluation of newer imaging biomarkers
• Evidence-based integration of imaging biomarkers with clinical and biochemical algorithms that lead to evidence-based protocols for imaging-based guided interventions and biopsies.
• Integrate preventive radiology at the primary, secondary and tertiary levels and with multimodality imaging replacing ex vivo tests as much as possible.
• Development of state-level committees and working groups to
• Organize state-level continuous medical education programs, workshops, and hands-on training
• Develop state-level trainers
• Provide training for radiologists in the state integrated with the PG curriculum
• Generate state-level data on the use and integration of imaging biomarkers and state-level evidence to inform algorithms
• Develop state-level clinical and preventive radiology research teams.
• Develop India specific guidelines and algorithms
• Develop Image biobanks for India.

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