88 A.A. Hayes-Jordan

Alternative Vertebrate Models

Zebrafish have become a popular and excellent model to study development, cancer, and genetics. The zebrafish has become prized because its transparent embryo develops out- side the mother’s body. This transparency allows minute to minute visualization of the cardiovascular, including blood flow,and structural changes that occur in“real time.”Because the zebrafish is a vertebrate animal, it has become a valuable resource for identifying genes involved in human disease.

Thomas Bartman and colleagues use the powerful tools afforded by zebrafish genetics to examine the early steps of heart valve formation. In the process, they provide evidence for a causal relationship between the early function of the heart and its final structure. Using a fluorescent molecular marker highly expressed in the developing heart, the authors found mutations that result in valve defects and identified a fish mutant they named cardiofunk (cfk).Genetic mapping of cfk showed that the abnormality was caused by a mutation in a gene encoding a novel actin molecule that is most closely related to the actins found in muscle cells.Actin is involved in muscle contraction; so these results suggest that muscle con- traction in the embryonic heart is intimately involved in heart development. Valve or septal defects represent 40% of car- diac anomalies in humans. By studying zebrafish, Bartman and colleagues suggest some of these defects may result from congenital defects affecting very early heart function.5

Zebrafish are being used to study cancer by Nancy Hopkins of the Massachusetts Institute of Technology. Her group has created over 500 lines of zebrafish with lesions in key genes involved in development and used them to identify a group of genes that predispose the fish to cancer. Using close observa- tion while cultivating some of these mutant lines, this team noticed that an abnormally large percentage of fish died young, whereas the surviving fish in these lines developed large, highly invasive malignant tumors. This ­facilitated the discovery of a ribosomal gene (rp) essential for embryonic development. Given the high degree of conservation of genes

andpathwaysamongvertebrates,it’spossiblethatrp­mutations also raise cancer risk in humans. Together, these results dem- onstrate that the tiny freshwater workhorse of developmen- tal biology has a promising future as a model system for human cancer.5

Selected Readings

Hanahan D. Dissecting multistep tumorigenesis in transgenic mice. Annu Rev Gene. 1988;22:479-519.

Wang YX, Mandal D, Wang S, et al. Inhibiting platelet-derived growth factor beta reduces Ewing’s sarcoma growth and metastasis in a novel orthotopic human xenograft model. In Vivo. 2009;23:903-909.

Fidler IJ. Seed and soil revisited: contribution of the organ microenvi- ronment to cancer metastasis. Surg Oncol Clin N Am. 2001;10: 257-269. vii-viiii.

Feretis C, Kalantzopoulos D, Koulouris P, Kolettas C, Chandakas S, Sideris M, Papalois A. Experimental studies of peroral transgastric abdominal surgery. Ann Gastroenterol. 2006;1:60-65.

Bartman T, Walsh EC, Wen KK, et al. Early myocardial function affects endocardial cushion development in zebrafish. PLoS Biol. 2004;2(5):E129.

92 C.C. Greenberg and J.B. Dimick

In this chapter, we will provide an overview of the field of

HSR in surgery,often also termed “surgical outcomes research.” Although this field is quite broad and could be depicted in several potential ways, we suggest a conceptual model that separates the field into three key components: (1) disease management; (2) the local micro-system in which treatments are provided; and (3) the policy environment (i.e., macro-system) in which health care is delivered. Each of these three key components is intimately related to one another to form the US health care system and can define the major scientific domains of HSR (Fig. 7.1). For each of the three major domains, we will provide a brief overview and discuss the intellectual disciplines (Table 7.1) and research tools (Table 7.2) necessary to conduct high-level studies in this area.

Patient-Level Questions: Evaluating

Disease Management

Overview

This domain of health services research aims to evaluate the management of disease at a population level under “realworld” conditions or from the patient’s point of view. HSR often provides important data that cannot be generated from

FIGURE 7.1 Conceptual model for the discipline of health services research (HSR). Panel A depicts how the key elements of our health care system interact: (1) disease management; (2) the local microsystem in which treatments are provided; and (3) the policy environment (i.e., macro-system) in which health care is delivered. These same three elements form the basic domains of the discipline of HSR, which is dedicated to understanding the system and approach to care provided at the individual patient, local, and health care delivery system levels. Panel B depicts the variety of intellectual disciplines that are considered health services research and how each relates to one of the three elements of the health care system or their intersection

94 C.C. Greenberg and J.B. Dimick

TABLE 7.1 The domains and intellectual disciplines that comprise health services research

treatment approach works outside of a controlled trial when all patients are considered. This area of HSR is primarily referred to as comparative effectiveness research. Another rapidly expanding area of HSR is patient-centered outcomes research. This area of research includes such important areas as quality of life, patient satisfaction, and shared decision-making. Data synthesis, including such techniques as meta-analyses and decision analyses, aims to answer questions