Ethical Issues in Testing and Test Development: What is the Role of the Pathologist?
Matthew J. McQueen, M.B.,Ch.B.,Ph.D.,FRCPC,HonFRCPath.
Professor, Pathology & Molecular Medicine, McMaster University,
Hamilton, ON Canada
2
Veterinary ethics combines veterinary professional ethics and animal ethics, with
the latter topic having a long history since the time of Aristotle1. The Veterinary
Profession has its own guidelines for professional ethics and the American Veterinary
Medical Association has a comprehensive series of Principles of Ethics2 The
International Association of Veterinary Editors has published Consensus Author
Guidelines on Animal Ethics and Welfare for Veterinary journals, updated in Geneva,
Switzerland, in 2010. The stated goal of these guidelines is to ensure that all material
published adheres to the highest ethical standards of animal welfare. Other countries
have also issued guidelines, which include those dealing with the differentiation
between animal research and veterinary treatment and the humane care and use of
animals for scientific purposes (New South Wales, Australia, Animal Ethics Infolink) 3.
This presentation will not discuss these areas since they have their own
academic base and they are taught in veterinary schools. The expression of issues of
ethics, autonomy, informed consent, beneficence, and truth-telling, as expressed in the
veterinary profession have drawn upon the extensive research done in medicine. The
professional relationship between physicians and their patients has essential similarities
to that between veterinarians and their patients and clients.
Beyond Professional Ethics.
One goal of this presentation is to see how veterinary pathologists react to a
criticism expressed some years ago that medical pathologists, clinical and
histopathologists, had an almost exclusive concern with technical problems, at the
expense of addressing the issues to which the technology could or should be applied 4.
Only veterinarians can answer if that criticism has any validity today in veterinary
pathology. The medical, moral and legal responsibility of the clinical physician was not
in dispute but the Laboratory Medicine professionals, whether as physicians or doctoral
level scientists, while having clear ideas about their professional ethics were less clear
and challenging as to their clinical and public responsibility and could be seen as having
followed a more passive and technical role. In opposition to following such a passive
role it was argued that public trust in clinical and anatomical pathologist professionals
was not only related to professional ethical standards but also to ethical responsibilities
demonstrated in the pursuit of the public interest and the common good. Translating
this into a veterinary context, the question could be asked, is the role of the veterinary
clinical or anatomical pathologist one of selling services or is it a professional calling of
providing service and, if the latter, can the line between professional identity and
citizenship be easily or clearly drawn?
Utilization of Laboratory Resources in Veterinary Care.
Veterinary testing is largely unregulated compared with human medicine.
Nevertheless, the clinical veterinary laboratory surely has a role in the responsible use
3
of finite resources by eliminating waste and acting to limit unnecessary testing.
Alternatively, is there a passive response, as was the case in many clinical laboratories
for many years, that if tests are requested by clinicians they are assumed to be useful
and had to be provided, even when the clinical or anatomical pathologist’s professional
expertise did not judge them to be useful. When test requests are too closely allied to
increased revenue in a fee-for-service situation or to increased allocation of resources
in a system receiving public funding, it seems to be the case that this issue takes a long
time to be thoroughly addressed and debated?
Great efforts have been devoted to proficiency testing and standardization in
medical laboratories to improve quality, yet in spite of this problems remain and
scandals have been uncovered. It may well be that there are no concerns about
inequality of service arising from the quality of work in veterinary laboratories if the
quality has already been demonstrated to be excellent. What would be less satisfactory
would be that the lack of concern was due to a lack of evidence on which any sound
judgment could be based. The call for evidence is a recurring theme in this paper.
For a variety of technology driven reasons laboratory testing has faced two
apparently contradictory pressures. One was to centralize and achieve economies of
scale, yet at the same time due to advances in biosensors and microprocessors, the
opposite process was to decentralize with point-of-care testing (POCT). This interesting
use of language tends to restrict rational discussion. Promoters of POCT can readily
portray any critic as showing a lack of caring. An alternative expression such as ‘point
of need testing’ would have emphasized rationality and the need for evidence. The use
of decentralized testing (POCT) should be guided by rationality, clinical need and cost
effectiveness, not by politics, power or profit. The potential advantages of decentralized
testing are clear since it may offer a faster turnaround time, more rapid clinical
decisions, avoidance of identification and transportation problems and increased
motivation of the individual performing the test. However, these theoretical advantages
should be investigated and their presence verified when any POC test is provided. The
veterinary clinical pathologist probably is the individual with the greatest understanding
of tests and their uses and limitations in veterinary practice. There is surely an ethical
and societal role to ensure that the client and the patient is being offered the most
clinically appropriate and effective test at a fair cost. An alternative test that is not
clinically superior should not be substituted simply because it is available as a POCT,
usually costing at least three to four times more than a centralized test. If the client is
told that the test is not superior and that getting it faster will make no clinical difference
to the management or outcome of the patient, but is still willing to pay the extra cost for
personal convenience then this is quite a different situation because the conditions of
informed consent have been met.
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Ethical and Design Challenges of Screening Programs and Screening Tests.
In medical practice the clinical pathologists and the doctoral level clinical
laboratory scientists, had a long history and experience of understanding laboratory
testing that unfortunately had not been drawn upon to improve the quality of screening
or testing programs. Only in the past 20 years have their voices been more clearly
heard in these areas5. More recently the voice of the anatomical pathologist has also
been heard in the area of test quality, addressing both the technical and interpretational
components. Clinical pathologists in veterinary medicine surely are in the best position
to understand the predictive value models for assessing test performance in their
clinical practice, all the models being based on the fact that as the sensitivity of a test
increases its specificity decreases and vice versa.
It has been suggested that if the consequences of any test or procedure are
uncertain it should be considered as research until its value and safety have been
established.6 Under common law any human patient has the right to receive
appropriate and understandable information in order to make a balanced judgment of
risks and benefits of any medical intervention, including new and established screening
programs. It would be hard to argue that the veterinary clinical pathologist, who is
offering and then performing various tests, does not have a similar responsibility
towards the client and the patient, particularly since any screening test is by definition
being used in a pre-symptomatic patient. The veterinary clinical pathologist knows the
analytical quality assurance of any screening test and when applying it clinically should
have knowledge of its efficacy, effectiveness, availability and efficiency for the condition
being screened. (Table 1). Similar to the medical clinical pathologist the veterinary
clinical pathologist has a role in understanding and evaluating the post-analytical
aspects of testing, the professional role is not limited to pre-analytical and analytical
concerns.
Clinical Efficacy
Does it do more good than harm.
Effectiveness
Compliance in the asymptomatic population.
Availability
Appropriate and adequate resources so that
It is readily available to many.
Efficiency
Appropriate and cost-effective use of resources.
Table 1. Categories of Scientific Evidence for and Against Screening.
The more abstract concepts embodied in the understanding of efficiency have also
been expressed as six clinically relevant questions which can be used to determine how
valid are various individual and multiphasic screening strategies (Table 2). The
questions, which have been drawn from medical practice, may require modification to
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be relevant to veterinary practice but there remains a need to meet the different design
and organizational challenges for good studies that can answer these questions.
1.
Can the screening maneuvers detect disease which is likely to have an important impact?
2.
Will the treatment of risk factors have a major impact on the development of the disease?
3.
How likely are participants to comply with treatment started as a result of the screening
program?
4.
Do existing screening programs alter the outcomes of the target disorder?
5.
Do some of the methods used in evaluating the clinical effectiveness of screening
programs lead to misleading conclusions?
6.
Have we fully considered all the possible long term effects of the screening procedures,
the negative effects of labeling people as having a disorder and the treatment started for
those found to be positive?
Table 2. Six clinical questions to determine the validity of individual and multiphase screening.
History of Screening in Medical Practice.
The history of screening in medical practice has provided many lessons. There
were at least 10 screening trials of early detection of lung cancer from 1950 until the
1970’s that showed no decrease in disease-specific mortality. Currently there has been
much publicity indicating that prostate cancer screening is challenged by evidence
pointing to it having a much more limited role. One concern is that it has resulted in
many unnecessary prostatectomies, with their accompanying side effects. The U.S.
Preventive Services Task Force concluded that PSA screening resulted in small to no
reduction of mortality for prostate cancer7.
Recommendations for the use of mammography in breast cancer screening have
been strongly promoted for many years, with more recent data now being cited that
indicate significantly less clinical value from this approach. The resulting changes in
screening recommendations have left many women very confused and even angry. It is
clear that professional enthusiasm to do good is by itself not sufficient.
There is ample evidence that many screening procedures were experimental, at
least in their early stages, and their strengths and weaknesses became apparent over
time. Informed consent should be as rigorous for a screening procedure as it is
expected to be for a clinical trial. The veterinary clinical pathologist has a role to play in
assessing the value of screening and screening tests in veterinary practice and by doing
so will retain the trust and confidence of the public. Such a strict interpretation of
consent undoubtedly produces opposition and many will try to counter it by the
suggestion that while all of the above may be true for tests that are potentially harmful, it
is not necessary to get informed consent for ‘harmless’ tests such as screening for
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increased cholesterol, or screening with other ‘routine’ tests which create no ethical
concerns. Concern with such statements arises because they seem to reflect no social
or ethical concerns about the costs of such testing, the absence of scientific evidence
that such testing has any benefit, and the apparent assumption that this type of
‘screening’ has no adverse effects on the patient, whether human or animal. Of the
adverse effects that may occur in humans those which are relevant to animals require
the expert reflection, research and discussion of the veterinary profession, but adverse
effects must be considered.
In 2000 the Canadian Task Force on Preventive Health published
recommendations for the screening and treatment of hyperhomocysteinemia in the
identification and management of coronary artery disease (CAD)8. They concluded
from more than 30 retrospective case-control studies and eight prospective, nested
case-control studies that there was an association but not a causal relationship between
homocysteine and CAD risk. They recommended against screening, but this did not
prevent clinical laboratories receiving many thousands of requests for this relatively
expensive test. However, a study which had clinical pathology involvement,
demonstrated in 2006 that although elevated homocysteine levels were significantly
lowered with folic acid, Vitamin B6 and Vitamin B12, this did not prevent vascular
disease events in high-risk patients.9 This conclusion was supported by other studies
and it was this evidence that within months reduced the test requests to a very small
number. The studies have not weakened the very strong association between
hyperhomocysteinemia and vascular disease but they clearly demonstrated that the
current therapy known to lower homocysteine levels did not produce any clinical benefit,
so there was no need to screen for something for which there was no effective
intervention.
Quality health care in both veterinary and medical practice must be based on
evidence to decide what is or is not appropriate. Evidence based evaluation requires a
systematic approach which involves understanding the concepts of the diagnostic
process, disease prevalence, ‘normality’, reference intervals, regression to the mean on
repeat testing, positive and negative predictive values, the diagnostic accuracy of
laboratory tests, clinical effectiveness and outcomes, together with the influence of
study design on the interpretation of outcomes10. These are not areas of arcane
knowledge restricted to epidemiologists and statisticians but are the tools of laboratory
science for the veterinary clinical pathologist to apply in veterinary medicine.
Appropriate Utilization of Laboratory Tests.
It is not possible to deal with this in depth but the experience of laboratory
medicine has been that the use of diagnostic resources has grown steadily and the
population health status has not been improving at a similar rate. Test ordering does
not seem to be influenced by the fact that in many cases the tests have poor diagnostic
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accuracy. Testing may simply be repeated and a cascade of testing may follow.
Guidelines and defensive behaviour produce more test requests11. There has been an
enormous growth in the theoretical underpinnings of the evaluation of diagnostic
procedures12, the challenge of communicating the accuracy of tests to general
practitioners13, and moving beyond diagnostic accuracy to show how it can be linked to
clinical utility14.
Concerns about variations in the use of laboratory tests with no clear correlation
with clinical outcomes, the excessive use or waste of laboratory resources and their
contribution to annual health care costs, predicted to be $4 Trillion in the United States
by the end of the decade,15 is driving many laboratory test utilization programs and
stimulating the publication of many ‘how to do it’ papers. However, there are clear
messages that the approach must be collaborative and inter-disciplinary and the
laboratory professionals must be engaged. It is recognized that utilization management
is in its early stages of development in the United States but the role of the clinical
pathologist and laboratory director is seen to be essential16,17. This is a societal issue
and while veterinary medicine may have some different issues, each with different
emphasis, it seems improbable that it would be immune to the fiscal pressures coming
from and being faced by the rest of society. For veterinary medicine the informed role
of the veterinary pathologist will be critical in the response to these challenges. Will it
be passive or professionally proactive?.
The Veterinary Pathologist and Clinical Research Ethics.
Outside our professional role we should care about clinical research ethics
because we may be involved as a research subject, and as citizens we need to be
aware that our prescription or our over-the-counter medicine may become part of a
database used in post-marketing research. In a professional capacity a veterinary
pathologist may be involved in a clinical trial or in the surveillance of side effects that
may arise in a clinical study. In clinical medicine formal approval is required for clinical
studies in many countries and national and international guidelines for good clinical
practice must be followed. However, in spite of this ethical breaches can and do still
occur. One example was in 1999 in a gene therapy trial at the University of
Pennsylvania in which Jesse Gelsinger18 who had a non-fatal genetic disorder was
enrolled in that trial. He had hypersensitivity to the treatment, was not informed of
changes in his liver function tests, he was re-challenged with the gene therapy vector
and died. In spite of all the supposed safeguards relating to informed consent,
information about deaths from liver injury in earlier animal studies had been withdrawn
from the patient information. Incidentally, none of the preceding patients had shown
significant gene delivery. The principal investigator held $13 million in equity in the
biotechnology firm that supplied the viral vector and the host institution had a substantial
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financial interest in the research. All of those factors were seen as areas of major
concern, and the system had failed to safeguard that young man.
Another example that clearly illustrates the complexity of the ethical challenges in
the collection, generation, and interpretation of clinical research data, was illustrated by
the history of the drug Rosiglitazone, which is used to control blood glucose 19. A metaanalysis of 42 studies of treatment with Rosiglitazone was published in 2007 which
suggested an increased risk of myocardial infarction or cardiovascular death for those
taking that medication. This meant that it took from 1999 when the drug was approved,
until 2007 to indicate that there was no cardiovascular benefit from the treatment but
apparently there was increased cardiovascular risk. The FDA decision to keep Avandia
on the market in this situation produced outrage in the U.S. Senate in 2010 28. The
issues of concern from 2007 until 2010 included the considerable delay in obtaining
information about health outcomes, and although there were tens of millions of
prescriptions for Rosiglitazone the FDA’s adverse event reporting system could not
detect risk of events as common as coronary artery disease. From a clinical laboratory
perspective there was an improvement in hemoglobin A1c, a surrogate endpoint and
not a hard clinical endpoint, which had been automatically translated into improved
patient health outcomes. There was also a lack of transparency in that the
pharmaceutical company Glaxo Smith Kline conducted a study in 1999 that suggested
Rosiglitazone might be less safe than a competing diabetes drug. These data were not
provided to the FDA during the initial 1999 review, nor when the meta-analysis was
reported in 2007. This was on a background of previous lack of transparency from the
company with the drug Paxil in 2004. Between 2010 and 2011 the FDA restricted
access to Rosiglitazone, it added cardiovascular risk, including myocardial infarction to
the physician labelling and patient medication guide. However, in 2013 the adjudicated
results of the study RECORD showed no elevated risk of myocardial infarction or death
in patients treated with Rosiglitazone. The medication was then made available with
indications for use that were similar to other diabetes drugs.
For those of us in clinical pathology involved in clinical research, this whole story
emphasizes the need to be knowledgeable about study design and it also made very
clear that data evaluation is a very complex area. There are also significant limitations
of meta-analysis. The strengths of the meta-analysis published in 2007 were that it
included unpublished studies, that it used major cardiovascular events, namely
myocardial infarction and cardiovascular death, as the primary outcome and did not rely
on a laboratory test and surrogate marker. It also did the analysis by comparing
Rosiglitazone with placebo. One major weakness of this meta-analysis was that only
summary trial-level data, not data from individual patients, was available and so it was
not possible to conduct time-to-event analyses or to evaluate the time course of risks.
Eligible trials included both placebo and active-treatment control groups. Across the
trials there was no standard method for identifying or validating the outcomes and so
9
events in eligible or ineligible trials may have been missed or misclassified. The total
number of events was very small with only 158 myocardial infarctions and 61
cardiovascular deaths. This meant that statistically there was little or no power to detect
potential differences among the trials if those differences were indeed present. The
result of inadequate power is that findings may be due to chance since a few events
either way might change conclusions. The later re-adjudication of the RECORD trial
illustrated that these were real weaknesses in the meta-analysis21.
The last example I want to give illustrates that even in the apparently highly
regulated world of human medical research major scandals can occur. In 2009 a
German anaesthetist, J. Boldt, published a paper related to cardiopulmonary bypass
priming using a high dose of a balanced hydroxyethyl starch versus an albumin-based
primary strategy. It was published in the Journal of Anesthesia and Analgesia and over
four weeks three readers questioned the “perfect” data. The Journal Editor then
requested investigation by the Ethics Committee for the German State of RheinlandPfalz, and it was found that there had been no Ethics Committee approval, there was no
evidence of written informed consent, and no prospective randomization in the study.
Investigation by the hospital and the State Medical Association then found no original
patient or laboratory data for the study. In fact albumin had not been used as a priming
solution since 1999 and the study was published in 2009. Boldt then admitted to forging
the signatures of co-authors, and in August, 2012, an extensive investigation concluded
that for 91 of his publications which they had studied, most had no evidence of ethical
approval and there was no, or incomplete, study documentation. Subsequently 16
medical journals retracted 89 of Boldt’s articles.
The clear messages here for all veterinary and medical pathologists involved in
clinical research are that despite guidelines and committees fraud can still occur. There
is an ethical obligation to ensure that there are tightened procedures, that there is
oversight to monitor such clinical studies, and pathologist researchers must play their
part in ensuring that quality standards are maintained. Furthermore, all authors must
sign that they have seen the original data and the authors must name the Ethics
Committee or Institutional Review Board that approved the study.
Improving the Reporting of Test Accuracy Studies.
In 2003 a group of medical clinical pathologists and laboratory scientists
produced the STARD statement which included a 25 item checklist to facilitate the
complete and transparent reporting of studies of the accuracy of medical tests. As all
laboratory specialists know these tests are key elements in many research studies and
publications22. The guiding principle in the development of the checklist was the
selection of items which would help readers of journal papers to find study results, judge
the potential for bias in the study and appraise the applicability of the study findings. It
was adopted by more than 120 journals, although it has to be admitted that there are
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variations in the extent that they recommend the use of the guidelines and their use of
the checklist. However, it has resulted in a significant improvement in reporting of test
accuracy studies. There is now a process underway involving the medical and clinical
pathologists and laboratory scientists to update the statement based on the experience
of using it for the past ten years. Apart from trying to make it easier to use by authors of
research publications, much more has become known in the past ten years about
sources of bias, sources of funding, sample size calculations, the use of optimistic titles,
rosy conclusions in the abstract and selective reporting of results. There is also a move
to make the language consistent with that used in clinical guidelines, and to promote the
idea that there should be a publicly available registry for all test accuracy studies, just
as has been advocated for all clinical trials.
All of these issues may seem remote to many veterinary pathologists but all
pathologists must be able to critically read papers and appraise the applicability of the
study findings in order to maintain their professional competence.
Bias in Research and Its Effect on Clinical Practice.
In the last ten years the number of publications in life sciences has increased
44%, and it appears that 80% of research publications attract no attention. It is
important to know something about the quality of the remaining 20% and the influence
of bias on those publications. Two studies indicated that 75% to 89% of pre-clinical
research studies, predominantly oncology related and published in top-tier journals
could not be reproduced23,24. There is an increasing incidence of published studies that
cannot be replicated and there is also an increasing incidence of corrections or
retractions. Some 235 forms of bias have been identified, clustered and mapped to
Biomedical Research Fields25. It has been shown that studies with favourable results
rather than negative or disappointing ones are more likely to be published. This is true
also for test accuracy studies, even those registered in ClinicalTrials.gov.26
Conclusion.
There are many ethical issues relevant to testing and test development, and the
veterinary pathologist has an active and important professional and ethical responsibility
in those areas. If studies are not designed and conducted properly there is an
unnecessary duplication of research efforts. When studies with more favourable results
are more likely to be published then this has a profound effect on the evidence-base for
clinical decisions since the profession is being presented with a skewed synthesis of
evidence. All of this produces biased estimates of the effectiveness of interventions and
results in unnecessary exposure of our patients to ineffective or harmful interventions.
As pathologists we must pursue the highest professional ethical standards. We must
also demonstrate our professional and ethical responsibilities in the pursuit of the public
interest and the common good.
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