LEARNING ANEW
| USE OF SIMULATORS IN LEARNING —John D. Mellinger, MD, Associate Professor of Surgery, Medical College
of Georgia, Augusta
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| Nonmedical example of approach to learning: goal—to learn to play golf and develop expert level of skill; method of
learning—going to professional golf course, acquiring set of clubs, and simply starting to play; problems with
approach—cost; performance pressure; risk to environment and to others; efficiency of learning process; access to
learning environment
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| Comments: this scenario how, historically, medical specialists (eg, surgeons) trained in technical skills (ie, placed in
high performance, high stakes environment; not allowed any time for development of skills other than on-the-job
training, then expected to perform at high level without hurting anyone); problems with this approach—20% drop-out
rate in surgical residencies; $50,000 cost in added operating room (OR) time per resident over course of training; adverse
outcomes; funding inefficiencies for general medical education (GME) in “post-Balanced Budget Act era”;
question of whether training possible in environment with restricted work hours
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| Challenges of medical education: to provide increasingly complex technical and cognitive training with—less financial
support; higher level of financial accountability; expectation of excellent patient outcomes; less time
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| Argument for use of simulation: compatible with adult learning and motor learning theory; safer (for learner and patient);
possibility of cost containment; criterion- and proficiency-oriented; potential answer to case-mix variation
(through standardization of experience); excellent research venue; excellent way to try out new techniques and technology
in safe environment; may eventually permit patient-specific rehearsal of procedures; Southern Illinois University
(SIU) experience
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| Elements of adult-learning theory: adult learners respond best if learning problem-centered, relevant, and conceptual;
supportive or safe environment (most adults do not learn or retain well in high-pressure setting); instruction must be
related to experience; feedback extremely important; learner must be active; Kolb cycle of experiential learning—
learner takes abstract concept and, by experimentation, turns it into concrete experience that brings learner back to
original concept
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| Elements of motor learning theory: key value of simulation providing structured way of doing deliberate practice that
clearly correlates with development of technical and motor skills; facilitators of motor learning—feedback (most effective
if given immediately); instructor support (instructor cueing can overcome information overload; support must
be balanced between too much and too little); practice scheduling (random; morning; 4 hr); specificity of practice
(should mimic real world conditions; however, fidelity much more important for expert learner)
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| Elements of expertise (Ericsson): quantity of practice determines attained level of performance and its maintenance;
practice at younger age better for developing technical skill; focused attention key aspect of deliberate practice (practice
without full concentration may result in inferior skill set); expertise more result of deliberate practice than of innate
ability or unique giftedness
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| Definitions: reliability—reflects degree of consistency; practically measured by testing and retesting under standardized
conditions (if this produces consistent results, test considered reliable); helps identify systematic and random errors in
process; validity—face validity (does simulation resemble skill in question?); content validity (is material covered in
sufficient breadth, and does it reflect what learner needs to know?); construct validity (can simulator distinguish learner’s
degree of skill?); concurrent validity (correlation with other established measures and tests of skill); predictive validity
(does result predict learner’s future performance, eg, does practicing with simulator make learner better clinical performer?)
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| Clinical impact of simulation training: study of midlevel surgical residents who received training in inguinal hernia
(IH) repair; 1 group got usual OR experience, 1 group got 10 30-min training sessions over 2 wk (video; CD ROM; inanimate
simulated IH repair model); subjects performed pre- and posttraining IH repair assisted by blinded surgeon
and evaluated by blinded surgical observer; both groups improved over time, but those who received simulated training
showed greater improvement (statistically significant)
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| Clinical impact of virtual reality training: prospective randomized study of 16 surgery residents (at various postgraduate
levels); all saw video on correct performance of laparoscopic cholecystectomy and had to demonstrate cognitive
understanding of video on multiple choice examination; test group received training (using minimally invasive surgery
virtual reality trainer [MIST-VR]) on manipulation of diathermy instrument used to dissect gallbladder off hepatic
bed during surgery; test group had to achieve proficiency level of experienced laparoscopist by end of
curriculum; standard group received usual surgery rotation instruction; residents then scored on performing mobilization
of gallbladder off of bed in OR by 2 blinded surgical observers; results—residents who received MIST-VR training
almost 33% faster; subjects who did not receive training 9 times more likely to not progress through procedure at
reasonable pace and 5 times more likely to burn extraneous tissue (gallbladder or adjacent liver); mean errors 6 times
less likely with training; demonstrates transference of skills developed in training into clinical realm
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| Transference: ability to extend what is learned in one context to another; cannot expect this to occur without mastery of
original subject or skill; affected by depth of comprehension (rather than simple rehearsal)
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| Flexible endoscopy simulators: 2 available and more in development; demonstrated to have face validity and construct
validity; 2 studies by Sedlack looking at gastrointestinal (GI) fellows in initial phase of training; compared performance
of novices trained on simulators with those who received no simulator training; found that fellows who
received simulator training did better in outcome measures on first 15 colonoscopies; however, advantages from training
negligible after 30 actual cases
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| Summary of data to date: little science yet to demonstrate effectiveness of simulators as they pertain to clinical practice
in GI disease; impetus for pursuing use of simulators consistent with principles of adult learning theory and challenges
of current educational environment
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| Concluding comments: national initiatives and directives in development call for technical skills training as part of medical
curriculum; barriers to simulator use—cost; requirement for additional personnel (eg, to run skills laboratory); time
for educational activity; duty hour restrictions; lack of validity; recommendations—use of simulators should be curriculum-
rather than device-driven; multiple departments should cooperate in sharing simulators; low-cost alternatives for
teaching skills; simulators will become routine part of surgical practice; next generation of simulators will be intelligent
tutors with virtual mentors to help teach skills more efficiently
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| PHARMACOGENOMICS: IMPORTANCE OF MINORITY ACCRUALS TO CLINICAL TRIALS —Timothy Synold,
PharmD, Associate Professor of Clinical and Molecular Pharmacology, City of Hope Comprehensive Cancer Center,
Duarte, CA
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| Introductory remarks: variability in patient populations one of key barriers to drug development; when group of patients
with same diagnosis treated with given drug, response variable; some do not respond; some develop unacceptable
toxicity and have to come off of drug; remainder of patients do fairly well; mandate for those involved in clinical
drug development is to identify these subsets of patients up front; would streamline drug development and enable
identification of those most likely to benefit from drug and eliminate patients who would be at risk or who would most
likely not benefit from treatment
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| Combination of isosorbide dinitrate and hydralazine (BiDil): may represent “first case of racial profiling” in medicine;
used in treatment of congestive heart failure (CHF); original clinical trials negative; subset analysis of data
showed better efficacy of drug in black subjects; subsequent trial of 1050 black subjects demonstrated 43% improvement
in survival; on this basis, Food and Drug Administration (FDA) approved drug for treatment of CHF in blacks
only; underlying biologic basis for efficacy in this patient population unknown
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| Factors contributing to variability in drug response: extrinsic (eg, sunlight; smoking; alcohol intake); intrinsic (eg,
liver function, kidney function); some argue genetic constitution primary underlying factor
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| Pharmacogenomics: defined as hereditary basis for individual differences in drug response; field of pharmacogenomics
began in late 1970s, with investigation of fainting response to debrisoquin (antihypertensive agent); researchers
able to establish response as heritable trait in 8% of patients given drug; now know that inheritable germline mutation
in debrisoquin hydroxylase, cytochrome P450 2D6 (CYP450 2D6) prevents metabolism of drug, causing very low blood
pressure and fainting; history of pharmacogenomic discovery—before era of genomics, genetic factors contributing to
response variability largely discovered through observational studies; in postgenomic era, researchers able to genotype
patients in advance of giving agent, and discover associations prospectively rather than retrospectively
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| Single nucleotide polymorphisms (SNPs) in human genome: 99% of human genetic sequence identical; 1% variation
accounts for differences among individuals; SNPs small genetic changes in person’s DNA sequence; to be defined
as SNP, change must be heritable and must occur in ≥1% of population; currently estimate close to 10million
SNPs in human genome; SNPs associated with functional changes in proteins encoded by exons (average of 2 SNPs
per gene); pharamacogenetics—some of these differences in genetic sequence influence how individual metabolizes
or transports drugs (affect clearance of drugs from systemic circulation); also SNPs associated with variable changes
in drug targets, ie, inherited differences in receptors or enzymes that affect sensitivity to pharmacotherapy
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| 6-Mercaptopurine (6-MP): most commonly used in maintenance phase in children who have advanced lymphocytic leukemia;
total amount of 6-MP that can be given to child during year of maintenance significant determinant of his or her
long-term survival; metabolic clearance of 6-MP varies up to 10-fold; clearance solely determined by genetic differences
in thiopurine methyltransferase (TPMT; enzyme that metabolizes drug through inactive thioguanine nucleotides); 3 principal
genotypes of TPMT associated with high, intermediate, or low enzyme activity; children with low or intermediate
enzyme activity at high risk for severe neutropenia, and given much less 6-MP in maintenance phase (dose has to be
withheld for long periods because of drug toxicity); labeling of 6-MP now changed to include statement that TPMT genetic
testing should be considered for patients with severe toxicity
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| Irinotecan: approved for treatment of advanced colorectal cancer; irinotecan converted by carboxylesterase into its
active metabolite SN-38; in liver, SN-38 inactivated by glucuronidation, via enzyme uridine diphosphate glu-
curonosyl transferase 1A1 (UGT1A1); patients with SNPs of UGT1A1 (*28 or *6 variant) have 2- to 4-fold decrease
in ability to glucuronidate SN-38; result—overall incidence of severe neutropenia in patients receiving irinotecan
10%; however, in patients homozygous for *28 variant, incidence 50%, and in patients heterozygous for variant, incidence
12.5%; patients homozygous for wild-type allele have low or no incidence of severe neutropenia; based on this
information, FDA has changed labeling of irinotecan, adding recommendation that patients known to be homozygous
for *28 variant should receive reduced starting dose; FDA now proposing that patients undergo prospective
genotyping for UGT1A1 polymorphism
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| Gefitinib (Iressa): small-molecule inhibitor of epidermal growth factor receptor (EGFR); received accelerated FDA
approval in 2003, based on response rate of 10% in patients with non–small-cell lung cancer (response rate of 30%
reported in Japanese patients); however, drug associated with 2% risk for interstitial lung disease (which has 30%
mortality rate); this led to much interest in identifying those patients likely to respond to gefitinib (could avoid
subjecting rest of patient population to drug’s severe toxicity); subsequently, researchers (Lynch and Haber) identified
genetic mutations in EGFR that could predict patient’s response (all mutations in tyrosine kinase domain of receptor);
although gefitinib received accelerated approval, definitive trial failed to show survival advantage; as result, FDA
changed labeling so that gefitinib now approved only for patients currently benefiting or who have previously benefited
and may continue to benefit from therapy
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| Comments: goal of pharmacogenomics to identify patients most likely to benefit from specific therapy; disadvantage for
drug companies that this reduces size of market; society (and drug industry) must grapple with whether developing drugs
for very limited populations based on pharmacogenomics makes economic sense
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| Future of pharmacogenomics: concept of “linkage dysequilibrium” (SNPs tend to be inherited in blocks); International
HapMap Project, multicountry group attempting to identify and catalog those sets of associated SNPs that provide
majority of information on genetic variations among individuals; preliminary findings show that although 10
million SNPs exist, 300,000 to 500,000 have almost all information about genetic variability
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| Concluding comments: genomics just one factor that leads to variability in drug response; some extrinsic factors (eg,
herbal medicines, diet) not only variable in population but also culturally linked; need to study most diverse population
possible to cover all factors that make patients react differently to drugs (ethnicity important covariant in drug response);
analysis of patient DNA now “ready for prime time” and now being used clinically; clear basis for use of
pharmacogenomics to aid clinical decision making; clinical trials needed because no good animal models for human
genetic variability; furthermore, early on in drug’s development, mechanism of action and toxicity often not fully understood;
major challenge in drug development—to ensure adequate representation of ethnicities in clinical trials; ultimate
goal to be able to give right drug at right dose to every patient
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Suggested Reading
Adamsen S et al: A comparative study of skills in virtual laparoscopy and endoscopy. Surg Endosc 19:229, 2005; Cisler
JJ, Martin JA: Logistical considerations for endoscopy simulators. Gastrointest Endosc Clin N Am 16:565, 2006; Clark
JA et al: Initial experience using an endoscopic simulator to train surgical residents in flexible endoscopy in a community
medical center residency program. Curr Surg 62:59, 2005; Dunkin B et al: Surgical simulation: a current review. Surg Endosc
21:357, 2007; Engen RM et al: Ethnic differences in pharmacogenetically relevant genes. Curr Drug Targets
7:1641, 2006; Ericsson KA, Lehmann AC: Expert and exceptional performance: evidence of maximal adaptation to task
constraints. Annu Rev Psychol 47:273, 1996; Ferlitsch A et al: Evaluation of a virtual endoscopy simulator for training in
gastrointestinal endoscopy. Endoscopy 34:698, 2002; Gerson LB, Van Dam J: Technology review: the use of simulators
for training in GI endoscopy. Gastrointest Endosc 60:992, 2004; Giacomini KM et al: Pharmacogenetics Research Network.
The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther 81:328,
2007; Greenwald D, Cohen J: Evolution of endoscopy simulators and their application. Gastrointest Endosc Clin N Am
16:389, 2006; Hamilton EC et al: Comparison of video trainer and virtual reality training systems on acquisition of laparoscopic
skills. Surg Endosc 16:406, 2002; Hamilton EC et al: Improving operative performance using a laparoscopic hernia
simulator. Am J Surg 182:725, 2001; Hochberger J et al: The use of simulators for training in GI endoscopy. Endoscopy
34:727, 2002; Krampe RT, Ericsson KA: Maintaining excellence: deliberate practice and elite performance in young and
older pianists. J Exp Psychol Gen 125:331, 1996; Marsh S, McLeod HL: Pharmacogenetics of irinotecan toxicity. Pharmacogenomics
5:835, 2004; Marsh S, McLeod HL: Pharmacogenomics: from bedside to clinical practice. Hum Mol
Genet 15 Spec No 1:R89, 2006; McLeod HL: Current overview of pharmacogenetics. Clin Adv Hematol Oncol 2:205,
2004; Moorthy K et al: An innovative method for the assessment of skills in lower gastrointestinal endoscopy. Surg Endosc
18:1613, 2004; Roden DM et al: Pharmacogenetics Research Network. Pharmacogenomics: challenges and opportunities.
Ann Intern Med 145:749, 2006; Scheeres DE et al: Animate advanced laparoscopic courses improve resident
operative performance. Am J Surg 188:157, 2004; Seymour NE et al: Virtual reality training improves operating room performance:
results of a randomized, double-blinded study. Ann Surg 236:458, 2002; Tan BR, McLeod HL: Pharmacogenetic
influences on treatment response and toxicity in colorectal cancer. Semin Oncol 32:113, 2005; Thomas FJ et al:
Pharmacogenomics: the influence of genomic variation on drug response. Curr Top Med Chem 4:1399, 2004.
Educational Objectives
| The goal of this program is to improve surgical training by incorporating the use of simulators and to expand the usefulness
of clinical drug trials by application of the principles of pharmacogenomics. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Cite the current challenges of medical education.
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| 2. Apply the principles of adult learning and motor learning theory in medical education.
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| 3. Discuss the arguments for the use of and potential benefits of simulators and virtual-reality training to medical
education.
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| 4. Describe current research in the mapping of inheritable polymorphisms within the human genome, and how
genetic variations influence drug metabolism and sensitivity.
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| 5. Explain the roles of pharmacogenomics and the inclusion of ethnicities in clinical trials, and their value as
components of drug development.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Mellinger is a consultant for USGI
Medical.
Acknowledgements
Dr. Mellinger was recorded at Medical and Surgical Approaches to GI Disorders, held July 10-14, 2006, in Kiawah Island,
SC, and sponsored by the Medical College of Georgia. Dr. Synold spoke at GI Conference 2006, held September 8-
10, 2006, in San Diego, CA, and sponsored by the City of Hope Comprehensive Cancer Center. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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