NATAP: The Role of Liver Biopsy, & Noninvasive tests
- Subject: NATAP: The Role of Liver Biopsy, & Noninvasive tests
Divining the role of liver biopsy in hepatitis C
Journal of Hepatology
Steven K. Herrinea, Lawrence S. Friedmanbcd
a Division of Gastroenterology and Hepatology, Thomas Jefferson University, Philadelphia, PA, USA
b Department of Medicine, Harvard Medical School, Boston, MA, USA
c Department of Medicine, Newton-Wellesley Hospital, Newton, MA, USA
d Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
See Article following this review.
Consensus is what many people say in chorus but do not believe as individuals.' Abba Eban, 1915
Since the first liver biopsy was performed by Paul Ehrlich in 1883 , the procedure has been a cornerstone of clinical hepatology as well as a lightning rod of controversy. Surveys in Europe and the United States indicate that a majority of liver biopsies are now performed as part of the evaluation of patients with chronic hepatitis C . Liver biopsy is useful for identifying those patients at highest risk for progression of hepatic fibrosis, thereby allowing selection of candidates most in need of (although not necessarily most responsive to) antiviral treatment. The procedure is considered safe, with moderate pain reported in 20% of patients, narcotic-requiring pain in 3%, vasovagal episodes in 2%, and severe complications, including bleeding, in 0.6% . Consensus statements from both the European Association for the Study of the Liver and the National Institutes of Health (NIH) recommend liver biopsy to aid clinical decision-making in patients with hepatitis C [4,5], thus
establishing examination of liver histology as the standard of care. The development of noninvasive techniques to estimate the degree of hepatic fibrosis , along with the increasing success of antiviral regimens [7,8], has led some experts to question the need for routine liver biopsy in the management of patients with chronic hepatitis C . To date, however, simple noninvasive tests of hepatic fibrosis, as well as more sophisticated proprietary fibrosis batteries, have not inspired sufficient confidence to displace reliance on hepatic histology [10,11]. Enthusiasm for liver biopsy has been tempered by the perceived risks, concern for patient discomfort, sampling error, and uncertain benefit in some subsets of patients, including those with persistently normal serum aminotransferase levels and those infected with hepatitis C genotypes 2 or 3.
In this issue of the Journal, Almasio and colleagues report on an investigation of experts' opinions on the use of liver biopsy in the management of hepatitis C . Using the Delphi method, which was originally developed by the U.S. Air Force as a method of consolidating expert opinion , the investigators, through the auspices of the Italian Association of Hospital Gastroenterologists, assembled a panel of experts on hepatitis C from the disciplines of gastroenterology, hepatology, infectious disease, and internal medicine. Twelve brief clinical scenarios were devised, and the experts were asked to offer their opinions on the appropriateness of liver biopsy in each situation. The results were then distributed among the experts, and a second round of questioning was undertaken in order to determine if consensus could be reached. What is most striking about the results is the lack of consensus on what we believe should have been straightforward decisions. For example, in case
number 9, a 30-year-old female with treated depression, genotype 2, and low viral load, 61.4% of experts elected to perform a biopsy, whereas 29.8% chose not to. As suggested in consensus statements, many hepatologists in the U.S. would now treat such a patient without first performing a liver biopsy because of the high likelihood of cure.
Other scenarios provided insufficient information to make an informed decision on the role of liver biopsy. For example, case 2 reads, 'Male, 40 years old, with persistently normal transaminases.' Missing from this summary is the estimated duration of infection, history of alcohol use, viral genotype, viral load, and presence or absence of other comorbid conditions, particularly psychiatric, that impact significantly on decision-making. Also missing from all the clinical vignettes is the preference of the patient, which often is the determining factor regarding whether to biopsy and whether to treat. In the NIH guidelines, liver biopsy is suggested for patients who wish to defer treatment . Given the limited clinical information, it is not surprising that the consensus building that is an integral part of the Delphi method did not occur with the single iteration of the process; the experts tended to hold their ground in each case. A study design that might have represented actual
clinical decision-making more accurately would have been longer and more cumbersome for the respondents, but would have yielded more useful information and may have allowed consensus to be achieved. Although the investigators rightly call for evidence-based evaluation of the usefulness of liver biopsy in the assessment of patients with hepatitis C, their implied recommendation to reign in the use of liver biopsy in the management of chronic hepatitis C seems premature.
Several other factors may have contributed to the inability of the experts to reach consensus on the use of liver biopsy and may have limited the generalizability of the findings. The Steering Committee that impaneled the experts and created the clinical scenarios was comprised of 'opinion makers within national organizations.' The Committee's lofty goal was to encompass representatives of all possible opinions from all groups who opine, although primary care physicians were not represented in the Delphi panel. However, the participation rate in the survey was low (56.5%) even though the participants were hand picked.
The subtlety that characterizes decision-making in clinical medicine is difficult to reproduce in brief case summaries. When the experts were asked to give their reasoning behind a choice of doing a biopsy or not, they had to pick from among several pre-formatted answers on a questionnaire. The reasons cited most commonly not to perform a liver biopsy in a U.S. survey study -perceived risk, low reimbursement, and logistical difficulties-were not even included as choices in the Delphi exercise. Many clinicians use the histologic information obtained by biopsy as a basis for advising patients against antiviral therapy , but this role for a liver biopsy was not addressed in the current survey. That differences in European and American health systems limit the generalizability of the data is demonstrated by the fact that 92% of the respondents perform liver biopsy as an inpatient procedure. In the U.S., the overwhelming majority of liver biopsies are performed as an outpatient
procedure. The role of internists and infectious disease specialists in the management of patients with hepatitis C also varies by region and health system. These differences in practice may lead to important differences in the perceived utility of liver biopsy. Finally, important common clinical situations that were not addressed in the Delphi exercise, including the non-drinking patient with physical evidence of cirrhosis, the elderly patient with no clinical signs of advanced liver disease, and the young adult with subacute infection, need to be considered before passing judgment on the overall value of liver biopsy in the management of hepatitis C.
Opinion regarding the use of liver biopsy in the management of chronic hepatitis C is likely to remain a moving target. One variable that may change the role of biopsy in the management of hepatitis C significantly is the further development of noninvasive measures to estimate liver fibrosis. Simple formulas that use readily available clinical and laboratory parameters are able to predict the degree of hepatic fibrosis with only modest accuracy; they are most useful for distinguishing cirrhosis from no fibrosis. For example, the AST/ALT ratio has a sensitivity of 31-56% and specificity of 90-100% for predicting cirrhosis but has little utility in estimating less advanced fibrosis . More sophisticated biochemical panels such as the Fibrotest are under study but have thus far yielded mixed results in the hands of various investigators [15-17]. A systematic review found that serologic test panels have sensitivities ranging from 50 to 82% and specificities of 35-80% . These tests,
in their current form, do not discriminate well among pre-cirrhotic stages of fibrosis; their main value is in distinguishing advanced fibrosis from no fibrosis . Results of imaging (e.g. magnetic resonance imaging) have been reported to correlate with liver fibrosis and may prove useful for predicting cirrhosis but are unable to provide information on pre-cirrhotic stages of fibrosis . Percutaneous transient elastography of the liver as a means of deriving a 'liver stiffness measurement' is a new technology that has shown reproducible correlation with histologic hepatic fibrosis . The sensitivity and specificity of this method can be increased when the test is used in combination with serologic assays to assess hepatic fibrosis . How well this technique will hold up to additional investigation remains to be seen. The future role of liver biopsy will also be challenged by the availability of new biomarkers of matrix metabolism that predict fibrosis and progression of
Ultimately, decision-making in patients with hepatitis C entails multiple considerations, of which the result of liver biopsy is only one. The telegraphic scenarios employed by the investigators may have been unable to provide the nuance that is so important in the management of patients with hepatitis C. The preference of the patient to undertake treatment that has an overall success rate of 55% and considerable toxicity can have considerable influence on the treatment decision. A clinician disinclined to recommend antiviral therapy in a particular case may still offer a liver biopsy to the patient who is uncomfortable with a passive 'watchful waiting' approach. On the other hand, the patient with persistently normal serum aminotransferase levels may be well served by interferon-based treatment if a liver biopsy specimen discloses an unexpectedly high histologic stage. Designating liver biopsy as unnecessary in specific scenarios may represent what the authors refer to as 'anatomic
prejudice' that denies the complexity of the decision-making. It is not unreasonable to consider all available methods, including liver biopsy, in any case. As long as histologic evaluation of the liver provides information that contributes to treatment decisions, the data remain potentially useful. Like the often cryptic prophecies of Pythia, Apollo's priestess at Delphi, information derived from a liver biopsy can be interpreted and applied in different ways. The authors are correct to call for evidence-based use of liver biopsy and studies of cost-effectiveness, but such goals should not blind us to the potential value of the procedure in any patient with hepatitis C.
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Experts' opinions on the role of liver biopsy in HCV infection: A Delphi survey by the Italian Association of Hospital Gastroenterologists (A.I.G.O.)
Journal of Hepatology
Piero Luigi AlmasioaCorresponding Author Informationemail address, Mauro Nierob, Donato Angiolic, Antonio Ascioned, Sergio Gullinie, Giorgio Minolif, Nadia C. Oprandib, Giovan Battista Pinzellog, Giorgio Vermeh, Angelo Andriullii
a Division of Gastroenterology, University of Palermo, A.O.U.P. Piazza delle Cliniche, 2, 90127, Palermo, Italy
b University of Verona, Verona, Italy
c San Donato Hospital, Arezzo, Italy
d Cardarelli Hospital, Napoli, Italy
e Santa Anna Hospital, Ferrara, Italy
f Valduce Hospital, Como, Italy
g Niguarda Hospital, Milano, Italy
h San Giovanni Battista Hospital, Torino, Italy
i Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
Background/aims: Liver biopsy represents the gold standard to establish a diagnosis in all liver patients, but its current position in chronic viral hepatitis is questioned. We aimed to create a consensus on best practice of use of liver biopsy in the management of chronic HCV infection.
Methods: We applied the Delphi method to 12 clinical scenarios of chronic HCV infection, to assess the extent of agreement (consensus measurement) and to resolve disagreement (consensus development) on the appropriateness of liver biopsy.
Results: Among 108 chosen hepatologists, 61 (56.5%) accepted to participate to the first-round survey. In four patients the majority of experts (from 61.4 to 86.2%) agreed not to perform liver biopsy; in two cases an equivalent opinion was found, and in the remaining six scenarios the majority of experts would have recommended a biopsy. No expert recommended liver biopsy in all cases, while most agreed for an histological evaluation of 4 to 8 cases. At the second round, 36 experts (59%) submitted ballots. Fifty-four out of 431 (12.6%) original judgments were changed with equal distribution among different scenarios.
Conclusions: Our survey showed a great divergence of management of similar patients and should provide a stimulus for an evidence-based evaluation of liver histology in chronic HCV infection.
Liver biopsy is considered the ultimate and most specific test to assess the nature and severity of liver disease, and represents traditionally the gold standard recommended to virtually all liver patients in their diagnostic work-up [1-4]. The striking advances in laboratory and virological investigations, immunological and genetic assays, and imaging procedures of the last years are now providing accurate non-invasive tools for evaluating the nature and activity of liver diseases and models predictive of liver fibrosis, which may dispense with a histological examination [5-7]. The requirement for a liver biopsy is becoming less absolute also in therapeutic decision making as histological uncertainties can be more tolerated with the newer antiviral therapies that are efficacious throughout the whole pathological spectrum of chronic viral hepatitis. Currently the usefulness of liver biopsy in chronic viral hepatitis is hotly debated, and experts' insights regarding the impact of
histological data in the management of these patients vary considerably.
The Delphi approach is a consensus development technique useful for situations where unanimity of opinion does not exist owing to lack of scientific evidence and experts' views are explored to enable decisions to be made on best practice [8-10]. Essential requisites of the method are anonymity, achieved by use of a questionnaire and private ranking; iteration which occurs through repeated 'rounds' allowing participants to change their opinions until the most reliable consensus appears to have been reached; controlled feedback, showing the distribution of the group's response; and statistical group response, expressing judgment using summary measures .
Recent guidelines issued by Scientific Societies on the management of patients with chronic hepatitis C recommend liver biopsy to be performed before consideration of treatment as it provides the most accurate means to determine the extent of liver injury [1-4]. Nevertheless, the published data that directly address this question are very limited. Different surveys of the current liver biopsy practice patterns have shown that a significant proportion of clinicians do not perform liver biopsies in patients with chronic hepatitis C [14,15]. In the current study the experts' willingness to recommend the procedure differed consistently among the 12 clinical scenarios, but it is important to emphasize that no surveyant required or did not require the invasive procedure in all cases. Experts' opinions were discordant between each others in respect of their attitude to recommend the biopsy, and one can presume that this variability is even greater in clinical practice situations. This
finding underscores that whereas guidelines dictate to act categorically, practicing physicians more carefully consider the procedure on a case-by-case basis. Indeed, in cases #1 and 5 surveyants were polarized in favour of the biopsy, whereas in case #2 they would not recommend it. Where guidelines on diagnosis and indications to treatment have been issued, i.e. as for the ideal patients represented in the previous three scenarios, the experts' in the present survey seem to adhere to them; consequently, a reasonably highly consistency among them was registered. Conversely, for the majority of the remaining clinical vignettes the consensus was low, and its level could not be increased by iterating the process, a finding which might be ascribed to lack of definite guidelines and divergent criteria in the literature.
As an important component of our Delphi survey the experts had to motivate reason(s) to recommend or not the biopsy. The three leading ones were to confirm the clinical hypothesis, to estimate prognosis, and to advise antiviral therapy, which were chosen by 42, 68, and 66% of experts. Conversely, main reasons to deny the procedure were the experts' perception that histological data had marginal or little impact on the pre-planned decision to treat the patient with antiviral therapy (indicated by 42% of surveyants), and their confidence to have attained a high level of clinical certainty by the non invasive evaluation of biochemical and ultrasonographic data (chosen by 22% of respondents).
How is it that opinions were so discordant among experts who tended to have a high degree of confidence in their opinion, even in face of contradictory views? Until now we have had a virtually free hand in the use of liver biopsy, a practice which stems from academic teaching that the ultimate diagnosis should rely on histological data, whereas clinical experience is always subjective and highly open to bias. This anatomical prejudice considers liver biopsy as the gold standard in the diagnosis of liver diseases, and eludes experimental observations that even the histological score for grading and staging liver inflammation is not devoid of subjective elements, of certain amount of inter- and intra-observer variation  and insufficient size of biopsy . The procedure has been embraced without a formal, experimental testing of its diagnostic accuracy. On the other hand, clinical experience is prone to making inaccurate casual connections and is thought to require objective data
in order to reduce diagnostic uncertainty. Such an attitude may comfort the patient and enhance the physician's desire to avoid malpractice claims, but do not necessarily produce more certainty in the validity of our diagnoses . It is important to understand the intrinsic limitation of either the anatomical approach and the empiric, clinical approach. We need to decide which level of certainty is to be attained in the management of our patients with chronic hepatitis C, while realizing that absolute certainty is unattainable, no matter how much information we gather.
Future studies in terms of cost-benefit analysis are essential to address the added value of histological data on the clinical diagnosis and on the outcome of antiviral therapy. Our survey showing that physicians manage similar patients with HCV infection very differently should provide a stimulus for evidence-based value of liver histology, in order to reduce differences and recommend liver biopsy in a uniform and appropriate fashion. This has implications for sparing patients the inconvenience and discomfort of testing that might not materially contribute do their care.
Any invasive procedure is only justified when it will change patient's treatment or management as during screening for hepatocellular carcinoma in case of cirrhosis, therefore it is futile to perform any examination just to satisfy a personal curiosity without any chance to change therapeutic program. In general the experts who decided to perform liver biopsy were forced by the need to make a prognosis and to optimize the treatment. conversely those who refused to make liver biopsy justified their decision with reliability of available clinical data and the need to avoid useless examinations. Therefore, the main dilemma is the degree of self-confidence by which we can take any decision on prognosis and therapy in chronic HCV infection and liver biopsy is a fundamental, but not indispensable, part of this decisional process.
Finally we think that other motivations to perform liver biopsy in clinical practice still persist and provoke some perplexity: routinely practices, a biased application of forensic medicine or to satisfy patient's indulgence. This is probably the domain on which the efforts will have to be concentrated to rationalize the use of the biopsy.
3.1. Characteristics of participating centers
Among 108 selected experts, 61 (56.5%) submitted the first-round ballot. Their centers were located throughout Italy, in particularly 48.5% in the North, 18.5% in the Centre, and 33.2% in the South of the country. The degree of expertise, as evaluated by number of years since the centre started to perform liver biopsy and the number of procedures performed each year, is shown in Fig. 1. Liver biopsy is very occasionally performed as an outpatient procedure (5 out of 61) and the other cases are equally distributed as day-hospitals or regular admissions. All centres execute a complete blood count and coagulation tests but only twenty requires blood group, while a very small proportion need a radiograph of the chest or an electrocardiography. About two third of Italian centres utilize Menghini needle with a diameter ranging from 1.2 to 1.6mm, the remaining admit the use of Tru-cut. Liver biopsy is performed under ultrasound guide only in 21 centres (34.4%) while the majority identify
the site of liver collection by previous ultrasound examination. Laparoscopy is performed only in two centres.
3.2. Delphi's first round
Table 3 provides the breakdown of the number of answers in favour or not to liver biopsy for the 12 clinical scenarios. In four patients (cases #2, 3, 9 and 12) the majority of experts (from 61.4 to 86.2%) agreed to perform liver biopsy; in two cases (#4 and 7) equivalent opinion whether to perform or not the procedure was found, and in the remaining six scenarios the majority of experts would have not recommended the biopsy. The highest rate of uncertainty (neutral responses) was registered in case #3. Overall, as many as 357 times liver biopsy was recommended and 290 times it was not. The motivations in favour or against liver biopsy are illustrated in Fig. 2. The three leading reasons to biopsy were to confirm clinical hypothesis, to estimate prognosis, and to advise antiviral therapy, which were chosen by 38, 64, and 60% of experts. Conversely, main reasons to deny the procedure were experts' perception that histological data had marginal or little impact on the pre-planned
decision to treat the patient with antiviral therapy (indicated by 42% of surveyants), and their confidence to have attained a high level of clinical certainty by the non invasive evaluation of biochemical and ultrasonographic data (chosen by 24% of experts).
3.3. Willingness to liver biopsy
The experts' attitude to perform liver biopsy ('willingness') was evaluated on the basis of number of positive answers across the 12 clinical scenarios (Fig. 3): no expert recommended liver biopsy in more than nine cases (willingness to biopsy), while the majority of them agreed for the histological evaluation between 4 and 8 cases.
In order to recognize which cases were more likely to undergo liver biopsy according to various degrees of expert's willingness, the probability for every case to obtain a positive answer is illustrated in Table 4. From this analysis, cases #1 and 5 were chosen by all the experts with at least six answers in favour of liver biopsy; moreover, among experts with a low attitude to biopsy (from 1 to 3 positive answers) no case showed complete agreement with a maximum probability of 0.50. In order to take into account the overall distribution of probabilities, the Pearson's 'r' shows that probability of a certain clinical case to undergo biopsy is strongly related to clinician's willingness to biopsy, except in clinical cases #2 and 10. As to the analysis of consensus, the H index is shown in Fig. 4: the highest consensus was reached in case #5 while the lowest agreement was in cases #4 and 7.
3.4. Delphi's second round.
At the second round, 36 experts (59%) submitted ballots. By comparing the frequencies of answers in favour or against liver biopsy throughout the two Delphi rounds, this subgroup of experts was considered representative of the initial group (Table 5). The overall numbers of positive, negative or uncertain answers were very similar after the feedback to the subgroup of the results in the first round (Table 6). However, 54 out of 431 (12.6%) original judgments were changed in the second round, with equal distribution of frequencies among the different scenarios. As to the consensus between rounds, Fig. 5 shows that it increased in clinical cases #2, 3, 6, 8, and decreased in cases #1, 3, 5, 9, 10 and was unchanged in cases #4, 7, 11, and 12.
An interesting aspect is the change in individual experts' opinion, which is shown in Fig. 6. Three ranks were recognized: marginal changes (cases #2, 3 and 5), small changes (cases #1, 4, 6, 9 and 11), and consistent changes (cases #7, 8, 10 and 12). For a better estimate of the degree of uncertainty, we cumulated the number of uncertain responses in the first round with that from changed answers in the second round (Fig. 7): case #10 still remained as the most controversial one, as far as agreement to biopsy was concerned.
2.1. The Steering Committee of the Delphi
The Italian Association of Hospital Gastroenterologists (A.I.G.O.) appointed eight leaders in clinical hepatology and gastroenterology, as evidenced by their roles as opinion makers within national organizations, to act as members of the Steering Committee on the indications of liver biopsy in patients with chronic hepatitis C. Panelists were recruited from diverse clinical disciplines involved in the diagnosis and treatment of these patients, including hospital-based gastroenterologists or hepatologists, University-based hepatologists, and internists. Among the Committee members, a diversity of viewpoints on the topic under investigation existed with four panelists sharing a strong, personal motivation towards a universal requirement of liver biopsy in the work up of these patients, and four having a more restrictive approach. Steering Committee members had to select the experts, and design the strategy for the Delphi, but were not allowed to participate in Delphi rounds. The
clinical panelists were joined by two experts on health science communication who provided expertise on the Delphi technique and developed a password-protected Web site that experts used to complete the Delphi rounds.
2.2. Selection of experts
Each member of the Steering Committee identified and invited at least 10 experts from their work in the appropriate area, with an emphasis on sampling similar number from north, centre and south of Italy. In order to guarantee a wide base of knowledge and to balance between referral and non-referral medical centers, invited experts were drawn from varied backgrounds including academic- or hospital-based divisions of gastroenterology, hepatology, infectious divisions and internal medicine, with either clinical or scientific expertise, and ensuring that no particular interest or preconceived opinion was likely to dominate. Although primary care physicians frequently evaluate patients with chronic viral hepatitis, none were included in the Delphi panel because they usually refer these patients to specialists, and are not allowed to recommend or execute a liver biopsy. Prospective experts were emailed an information package containing a synopsis of the study goal, a description of
Delphi, and a Microsoft Access questionnaire about 12 clinical cases of HCV infection.
2.3. Delphi items
Anchoring clinical scenarios (we shall also call clinical cases) were selected for the Delphi survey . Important requirement for this strategy was that the same clinical scenarios will be presented to all respondents, irrespective of their attitude toward the liver biopsy (scenarios equivalence), and that an individual expert had to use the response categories for a particular question in a similar way (response consistency). Attributes of such scenarios were the following: age, sex, alcohol consumption, peculiar features of past and present clinical history, physical examination, laboratory and instrumental data. Twelve records of patients with chronic HCV infection, were selected from a pool of 50 prepared by the Steering Committee. Table 1 illustrates the clinical scenarios that were used for the Delphi survey. The choice of the scenarios was dictated by their relative frequency encountered in the everyday clinical practice.
We applied a modified Delphi method to 12 clinical scenarios of chronic HCV infection, in order to assess the extent of agreement (consensus measurement) and to resolve disagreement (consensus development) on the appropriateness of liver biopsy in the management of patients with chronic hepatitis C.
Table 1. Clinical scenarios of patients with chronic HCV infection used in the Delphi' survey, with a brief description of relevant features
Case 1 Male, 27 years old, moderate alcohol drinker, no clinical evidence of progression to cirrhosis, and high probability of treatment response.
Case 2 Male, 40 years old, with persistently normal transaminases.
Case 3 Male, 53 years old, moderately alcohol and smoking consumer, with clinically established cirrhosis.
Case 4 Male, 63 years old, moderate alcohol drinker, on treatment for essential systemic hypertension, with low probability of treatment response (genotype 1b and high viral load, long history of infection).
Case 5 Male, 52 years old, moderate drinker but heavy smoker, with controlled diabetes by therapy and high values of serum iron bound to transferrin.
Case 6 Female, 28 years old, past drug addiction, HIV seropositivity under HURT since 12 months.
Case 7 Female, 56 years old, hyperthyroidism under treatment with tapazole, and low platelet count.
Case 8 Male, 33 years old, blood transfusion at birth, no clinical and instrumental evidence of advanced liver disease.
Case 9 Female, 30 years old, drug-treated depressive syndrome, and high probability of response to therapy (genotype 2a/2c, low viral load).
Case 10 Male, 40 years old, alcohol and smoking consumer, obese (>30 BMI) and dyslipidemia.
Case 11 Male, 49 years old, diagnosis of mild chronic hepatitis ten years before, relapse after Interferon therapy, no evidence of progression to cirrhosis.
Case 12 Male, 58 years old, long-lasting heavy drinker.
In the first Delphi round each expert evaluated each of the 12 clinical vignettes, and was asked to answer the question whether he/she would or would not agree, or would be uncertain whether to perform a liver biopsy. Furthermore, each expert had to motivate his/her choice by answering a series of questions, part as pre-formulated answers, part as free-fields. The pre-formatted answers are shown in Table 2. Every expert could indicate more than one choice among the list of answers. For those who were uncertain about their final decision, an open field for their answers was provided. After completing the answers of a single clinical case, a new questionnaire with the same mask automatically started, describing a new patient. Each expert could go back to a previous questionnaire and possibly correct or review its own answers.
In the second round the experts considered the same 12 clinical vignettes, and this time were also informed what the experts' answers were for each vignette in the first poll. Moreover during the discussion within the Steering Committee about the results of the first round, 'neutral' comments regarding the motivations for 'yes' or 'no' were added to the questionnaire. The panelists were asked to evaluate the clinical vignettes again in light of this information, and to state whether or not they would confirm or change their original answers. If they would have changed their previous judgments, an explanation for the changes should be included. The process was terminated after the second round.
2.4. Analysis of Delphi data
For the first round 108 questionnaires have been sent to the experts. Practical management of mailing and solicitations have been under the supervision of an external partner (Health Outcomes Research, Padua, Italy). Each member of Steering Committee could not access to individual data but only to summarized results.
The overall data of Delphi questionnaires of the first round were stored in a data base to be subsequently analyzed and summarized by SPSS software.
2.5. Statistical analysis
Monovariate and bivariate statistics were produced. Agreement-consensus among experts is usually measured through a variability index. Being possible responses Yes-No-Neutral about performing biopsy, we used a heterogeneity index (H) for categorical variables . This index scores H=0 when all panelists give the same answer (yes, or no, or neutral), meaning that the consensus is maximum; H=1 when all respondents are equally distributed throughout the three response choices, meaning that the consensus is minimum. Additional statistics concern willingness to biopsy by the experts and their change of opinion between rounds.
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