Preface

The knowledge-driven medical research paradigm is encountering bottlenecks. A paradigm refers to a collection of academic elements that are commonly followed by a scientific community. These elements include values, basic theories, laws and regulations, practical norms, technical standards, and exemplary examples. Since the Renaissance, medical research has mainly formed two paradigms: a knowledge-driven research paradigm and a problem-driven research paradigm. The former has always played an important role in the development of medical systems. Under this paradigm, medicine is divided into independent knowledge systems. Medical subdivisions accelerate the creation, accumulation, iteration, and sublimation of knowledge, and promote the systematic construction and improvement of medical knowledge systems. In a relatively closed discipline system, researchers, motivated by their curiosity and thirst for knowledge, freely think about and choose topics for research, emphasize the non-utilitarian and non-social attributes of knowledge, and recognize that the progress of theoretical knowledge has endless application prospects. This innovation model driven by knowledge exploration has promoted the development of modern medicine and the progress of human health care. The well-known milestones of modern medicine, such as the theory of evolution, cell theory, and the principle of life center, are all important academic products under the knowledge-driven research paradigm.

The physiological function and pathological changes of the human body are highly complex. From molecules, cells, tissues, organs, and systems to the human body, these system functions are regulated by multiple factors in a multidimensional manner and depend on the nonlinear interaction between components. It is difficult to reveal and analyze the complex physiological and pathological mechanisms and evolution laws of the human body using traditional research methods dominated by reductionism. In the face of the medical problems of complex diseases such as malignant tumors, cardiovascular and cerebrovascular diseases, and coexistence of multiple diseases brought about by the aging society, the existing research models, such as fragmentation, low dimension, and reductionism, are even more difficult to use to make major breakthroughs.

Obviously, the knowledge-driven scientific research paradigm has formed disciplinary barriers between knowledge systems, resulting in the lack of systematic thinking and methods in scientific research, encountering difficulties in solving complex medical problems, and significantly weakening the contribution to social economy. The further tilt of biomedical research investment has not brought significant improvement in people's well-being.

In addition, another reason the knowledge-driven paradigm is so controversial is that it relies on such indicators as papers, academic qualifications, and academic titles as evaluation criteria. From the statistical data, with the advance of the years, scientific research investment was carried out according to the knowledge-driven model. The value of medical research can be embodied and disseminated through papers, but

papers should not be the purpose of medical research. We need papers because they can help more peers share and apply valuable knowledge and technology to benefit patients.

The problem-driven medical research paradigm is gaining acceptance quietly. In this paradigm, "problems" play the leading role in research. Here, "problems" refer to the practical problems that restrict social and economic development. Therefore, academic research under the problem-driven scientific research paradigm has a strong social attribute and utilitarian color. It is not for the sake of improving the knowledge system of a single discipline but is more focused on whether to solve the problems in social and economic development. The goal is to meet practical needs by developing new and practical scientific and technological products, and thus this paradigm is more suitable for interdisciplinary systematic research.

This problem-solving research can generate rich and useful knowledge in theory and technology, stimulate the development of relevant traditional disciplines, and promote the generation of new interdisciplinary and marginal disciplines through "discipline interaction." Compared with knowledge-driven research, the evaluation criteria of problem-driven research are more diversified, and need to be judged from two basic aspects: practicality (usefulness) and scientificity (rationality). It depends not only on published research papers but also on the academic, social, and economic values of scientific research achievements. It also depends on what benefits a medical research achievement really brings to patients and what benefits it creates for the social healthcare service system. "Research without innovation is nonsense, research without products is futile," which fully reflects the core values of the problem-driven research paradigm.

The problem of people's health needs is the main battlefield of current medical research. Scientific research separated from clinical problems is a tree without roots and water without a source. Clinical problem-driven research (CDR) is a way to identify problems through clinical practice and then define the scientific and technical problems therein. Carrying out clinical research or transforming medical or scientific research results in the development of diagnosis and treatment standards and products, practice guidelines, innovative drugs, medical equipment, and more for clinical verification, evaluation, and optimization.

The era of the knowledge economy has higher requirements for "integration of science, technology and economy." Therefore, under the CDR paradigm, we also emphasize the health product-oriented (Bedside to Bench to Clients, B2B2C) research and development model. The ultimate goal of clinical research is not to publish papers, but to produce health technology products with practical value, providing inexhaustible momentum for the sustainable development of the health industry, so as to form clinical research. The positive interaction between medical practice and industrial development is a closed loop.

Therefore, medical science and technology innovation will gradually shift from a knowledge-driven research paradigm to a clinical-driven research paradigm. At present, a new round of scientific and technological revolution and industrial transformation is reshaping the global innovation landscape and economic structure. Scientific and technological innovation is characterized by intersection, integration, penetration,

**V**

patients.

neurosurgery.

and radiation. Disruptive technological innovation is constantly emerging. Scientific big data is becoming a new scientific research model following experimental science, theoretical analysis, and computer simulation. System medicine with data intelligence as the core technology in the medical field will strongly promote the steady development of CDR characterized by disciplinary integration and systematic research.

Academic physicians are leaders in clinical-driven research. Clinicians are on the front line of clinical practice and are the primary discoverers of clinical problems. An outstanding academic clinician should always take scientific and technological innovation as their mission and responsibility for career development, and should not be satisfied with treating patients only with existing knowledge. We should pursue knowledge creation and technology innovation and play a leading and integrated role in clinical research. Through the research strategy of "finding problems, initiating research, establishing projects by consensus, communication and cooperation, finding good strategies, and applying evaluation," we should solve the problems and pain points in practical health care and continue to improve the level of medical services

As an endovascular neurosurgeon, I also have some ideas about the growth and development of academic doctors. Surgical clinical work is faced with the challenge of complex and difficult diseases that cannot be solved by traditional clinical thinking and surgical methods. Behind the clinical challenges are the scientific and technical issues in surgical practice. In terms of scientific issues, it is necessary to seek systematic intervention rules for multi-objective optimization, and in terms of technical issues, it is necessary to explore deterministic intervention technologies to achieve multi-objective optimization. Through clinical research, we established the maximum intersection theory, namely, the three elements balance rule, under the collaborative constraint of seeking lesion clearance, nerve protection, and nerve damage control. At the same time, we have carried out innovation and practice of deterministic neurointerventional technology, using visualization, quantification, and controllability technology to overcome factors that are difficult to determine, predict, and control in traditional empirical neuro-interventional clinical practice. We achieved a balance of three elements in clinical practice with accurate decision-making and application of appropriate intervention methods to obtain safe, efficient, and minimally invasive multi-objective optimization. The ultimate goal is to maximize the health benefits of

Based on the exploration and practice of continuously improving the effect of endovascular therapy for complex cerebral and spinal vascular diseases, I put forward the concept of "precision endovascular neurosurgery," built a precision endovascular neurosurgery paradigm, solved a series of difficult endovascular therapy problems for complex cerebral and spinal vascular diseases, and promoted the level of endovascular

Lao Tzu of *Tao Te Ching* says, "A tree that is hugged is born at the end of a centimeter; a platform of nine layers begins with a pile of earth; a journey of a thousand miles begins with a single step." It is the responsibility and mission of clinicians to lead clinicaldriven research. The process from clinical practice to theoretical and technological innovation is also an important transition process for clinicians from "craftsman" to "home." Clinical-driven research must be supported by the innovative system of

and quality of care for patients.

and radiation. Disruptive technological innovation is constantly emerging. Scientific big data is becoming a new scientific research model following experimental science, theoretical analysis, and computer simulation. System medicine with data intelligence as the core technology in the medical field will strongly promote the steady development of CDR characterized by disciplinary integration and systematic research.

Academic physicians are leaders in clinical-driven research. Clinicians are on the front line of clinical practice and are the primary discoverers of clinical problems. An outstanding academic clinician should always take scientific and technological innovation as their mission and responsibility for career development, and should not be satisfied with treating patients only with existing knowledge. We should pursue knowledge creation and technology innovation and play a leading and integrated role in clinical research. Through the research strategy of "finding problems, initiating research, establishing projects by consensus, communication and cooperation, finding good strategies, and applying evaluation," we should solve the problems and pain points in practical health care and continue to improve the level of medical services and quality of care for patients.

As an endovascular neurosurgeon, I also have some ideas about the growth and development of academic doctors. Surgical clinical work is faced with the challenge of complex and difficult diseases that cannot be solved by traditional clinical thinking and surgical methods. Behind the clinical challenges are the scientific and technical issues in surgical practice. In terms of scientific issues, it is necessary to seek systematic intervention rules for multi-objective optimization, and in terms of technical issues, it is necessary to explore deterministic intervention technologies to achieve multi-objective optimization. Through clinical research, we established the maximum intersection theory, namely, the three elements balance rule, under the collaborative constraint of seeking lesion clearance, nerve protection, and nerve damage control. At the same time, we have carried out innovation and practice of deterministic neurointerventional technology, using visualization, quantification, and controllability technology to overcome factors that are difficult to determine, predict, and control in traditional empirical neuro-interventional clinical practice. We achieved a balance of three elements in clinical practice with accurate decision-making and application of appropriate intervention methods to obtain safe, efficient, and minimally invasive multi-objective optimization. The ultimate goal is to maximize the health benefits of patients.

Based on the exploration and practice of continuously improving the effect of endovascular therapy for complex cerebral and spinal vascular diseases, I put forward the concept of "precision endovascular neurosurgery," built a precision endovascular neurosurgery paradigm, solved a series of difficult endovascular therapy problems for complex cerebral and spinal vascular diseases, and promoted the level of endovascular neurosurgery.

Lao Tzu of *Tao Te Ching* says, "A tree that is hugged is born at the end of a centimeter; a platform of nine layers begins with a pile of earth; a journey of a thousand miles begins with a single step." It is the responsibility and mission of clinicians to lead clinicaldriven research. The process from clinical practice to theoretical and technological innovation is also an important transition process for clinicians from "craftsman" to "home." Clinical-driven research must be supported by the innovative system of

academic hospitals. At present, under the clinical problem-driven research paradigm, medical research and medical services are often "two skins." There are still many problems between them, such as differences in professional direction, lack of cooperation channels, difficulties in transformation and application, and contradictions in achievement sharing. There is an urgent need to reconstruct the organizational model and ecosystem of medical science and technology innovation and the links between basic research, clinical research, transformation research, and industrialization.

We would like to thank all the authors for their contributions. We would also like to acknowledge the encouragement, motivation, and assistance from the Beijing Municipal Administration of Hospitals Incubating Program (PX2020039), China, and Tsinghua Precision Medicine Foundation (20219990008), Tsinghua University, Beijing, China.

#### **Xianli Lv**

Section 1

Design of Clinical Trial

Neurosurgery Department, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
