Clinical Chemistry 46: 1091-1098, 2000;
(Clinical Chemistry. 2000;46:1091-1098.)
© 2000 American Association for Clinical Chemistry, Inc.
Opportunistic Discovery of Occult Disease by Use of Test Panels in New, Symptomatic Primary Care Outpatients: Yield and Cost of Case Finding
Yuzuru Takemura1,4,a,
Haku Ishida2,
Yuji Inoue3,
Hiroyuki Kobayashi1 and
J. Robert Beck4
1
Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
2
Department of Clinical Pathology, Kawasaki Medical
School, Kurashiki, Okayama 701-0192, Japan.
3
Department of Medical Informatics and Decision Sciences,
Yamaguchi University School of Medicine, Ube, Yamaguchi 755-8505,
Japan.
4
Pathology/Information Technology Program, Baylor College
of Medicine, Houston, TX 77030-3498.
a Address correspondence to this author at: Department of Laboratory Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Fax 81-42-996-5217; e-mail yutakemu{at}interlink.or.jp
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Abstract
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Background: Diagnostic test panels have been advocated by the
Japan Society of Clinical Pathology for evaluation of presenting
complaints of new outpatients in primary care medicine. The tests have
additional potential utility for opportunistic finding of asymptomatic
diseases, but data are lacking on the number of new conditions
identified by the test panels and on the cost per identified
case.
Methods: We studied 540 new, symptomatic patients at the
Comprehensive Medicine Clinics of National Defense Medical College
during 1991–1997. All underwent testing with the "Essential
Laboratory Tests" panel (2) [ELT(2) panel]. This panel includes
hematologic tests, urinalysis, total protein, C-reactive protein,
albumin, cholesterol, triglycerides, glucose, urea nitrogen,
creatinine, uric acid, serum protein fractionation, six enzymes, and
optional tests, including x-rays, electrocardiogram, and fecal occult
blood.
Results: The ELT(2) panel uncovered 276 additional diagnoses of
asymptomatic disease or abnormal health status. The most frequent
occult condition was hyperlipidemia (100 cases) followed by liver
dysfunction (53 cases). Clinical efficiency of the panel (occult
diseases/patient) varied depending on the category of tentative initial
diagnosis, with the highest efficiency in patients with cardiovascular
disease. We created smaller panels by combining 11 basic tests [called
the ELT(1) baseline panel] with one or more additional tests from the
ELT(2) and analyzed their cost-effectiveness. Addition of four tests
(total cholesterol, alanine aminotransferase, glucose, and uric acid)
improved both clinical efficiency (0.41 occult disease/patient) and
economic efficiency [¥2372 (~$22.50 US)/occult disease] at a
cost-effectiveness of ¥177 per incremental case of occult disease.
Addition of further tests decreased cost-effectiveness.
Conclusions: Although the ELT(2) panel has supplemental utility
for opportunistic screening of some significant, occult diseases and
conditions, universal utilization of the full panel is not supported by
the cost-effectiveness found in this study.
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Introduction
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The Japan Society of Clinical Pathology
(JSCP)1
has developed practice guidelines for efficacious test
utilization to compete against the rapid expansion of diagnostic test
usage in the past two decades in Japan. The JSCP subcommittee has
established a panel test system to be applied to every new outpatient
in primary care medicine, designating the test packages as the
"Essential Laboratory Tests (ELT)" panels. The ELT panels,
according to the JSCP, should be performed at the initial clinical
evaluation of new outpatients regardless of the clinic or patient’s
disease categories in parallel with a history and physical examination
(1). The ELT panels are composed of two panels, ELT(1) and
ELT(2), the compositions of which are shown in Table 1
; the JSCP intends for the ELT(1) basic panel to be universally
ordered at the first evaluation of new primary care outpatients as
routine testing to obtain minimally essential information for a disease
or patient’s physical condition, whereas the ELT(2) panel tests,
including optional chest and abdominal plain x-rays and
electrocardiogram (ECG), should be performed selectively to focus the
initial clinical diagnosis if necessary.
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Table 1. Common diagnostic tests performed for new outpatients
visiting the Comprehensive Medicine Clinics, National Defense Medical
College and its affiliated hospital.
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In our previous study (2), we analyzed the
cost-effectiveness of the ELT panels for providing information that
contributed to a change in a physician’s tentative initial diagnosis
(TID) or in a physician’s decision-making in new outpatients with
symptoms. The utility of the ELT panels varied widely among patient
groups, with the highest yield (in patients with hematologic disease)
20-fold higher than the lowest yield (in patients with neurologic
disease) (2). Despite the JSCP’s recommendation, we
concluded that selective test combinations should be used for selected
patient groups. In that study, however, we did not assess an additional
potential advantage of a panel test system, i.e., its utility for
identification of occult disease. Although the JSCP guideline stated
that the panel test system should be directed to new primary care
outpatients with defined symptoms for the purpose of clinical
evaluation of a patient’s illness, the ELT can uncover unforeseen,
additional disease(s) unrelated to a patient’s chief complaint.
Therefore, the enforcement of the ELT panel testing also provides an
opportunistic screening for some occult diseases among a symptomatic
patient population.
In the current move to avoid unnecessary testing in the United States
and other countries, panel testing is discouraged and efforts are made
to use more carefully selected individual tests or small groups of
tests. Screening-test profiles without distinct cost-effectiveness have
not been generally accepted (3)(4)(5). Certainly, there may be
a consensus that screening-test profiles for occult disease detection
should not be applied to healthy populations without symptoms or risk
factors for a disease (5)(6). Furthermore,
screening tests may have potentially harmful effects from
false-positive or -negative results (7). However,
identification and early management of silent but significant diseases
such as dyslipidemia and diabetes, which frequently require high-cost
medical care at the symptomatic stage, may ultimately be
cost-effective: early discovery of a disease can lead to its arrest,
reversal, or cure, and thereby decrease morbidity and mortality
(8), reducing overall costs for total medical care. Although
one of the current principal tenets of the third-party payers of health
insurance is to eliminate unnecessary testing, elimination of some
tests may increase the total cost of medical care. The Medicare billing
regulations that became effective in April 1998 allow small panels such
as lipid profiles based on automated multichannel analyzers
(9). Nevertheless, there are very few studies that
accurately analyze cost-effectiveness for opportunistic screening of
asymptomatic, occult diseases.
In the present study, we evaluated the clinical and economic
efficiency2
of the ELT panels for opportunistic finding of occult disease
in symptomatic patients. We discuss this utility of the JSCP panel test
system separately from its validity for clinical evaluation of
manifested diseases.
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Patients and Methods
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Patients
Among all new outpatients who visited the Comprehensive Medicine
Clinics, National Defense Medical College, Tokorozawa, Japan and its
affiliated hospital from June 1991 to March 1997, 540 patients (250
males, 290 females; age range, 9–83 years) who had defined symptoms
and who were seen by physicians certified by the Japanese Boards of
Internal Medicine and Clinical Pathology were entered in this study.
Patients were eligible irrespective of their symptoms or disease
categories, without any selection process except for those referred by
physicians in other medical facilities with test results and/or
tentative clinical diagnoses. These patients were excluded in advance
from the study or not evaluated in the analyses. Patients were
universally given a diagnostic test package corresponding to the ELT(2)
(Table 1
) with the addition of serum cholinesterase after a history and
physical examination. Diagnostic sensitivity, specificity, and positive
predictive values of the individual panel components were analyzed in
our preliminary study and described elsewhere (10). Chest
and abdominal plain x-rays, ECGs, fecal occult blood tests, and
serological tests for hepatitis-related virus antigen or
antibody and syphilis were optional choices. Diagnoses were
divided into the TID, which was tentatively made by the primary
care physician from the history and physical examination alone, and the
"initial clinical diagnosis" which was established after
integrating the results of diagnostic tests. A diagnosis related to a
patient’s chief complaint was defined as the "primary diagnosis or
disease", whereas those uncovered by abnormal test results that were
unexpectedly elicited by the enforcement of the ELT and not related
directly to a patient’s illness were defined as "additional
diagnoses or occult diseases". An "occult disease" indicates a
silent but clinically significant disease, whereas a patient’s
asymptomatic abnormal health condition, which has subclinical or
uncertain significance but influences a physician’s decision-making,
is designated as an "occult abnormal health status" uncovered by
the test results.
Assay methods and diagnostic criteria for occult diseases
Assay methods for the common diagnostic tests performed have been
described in detail elsewhere (2). Briefly, chemistry tests,
complete blood count and leukocyte differential count,
C-reactive protein (CRP), sialic acid, and serum protein profiles
(protein fractions) were analyzed on automated multichannel analyzers.
Because sialic acid is considered a delayed responder to inflammation
and to show a different movement in the inflammation process from CRP,
this test is also adopted in the ELT(2) panel. Dipstick urinalysis was
performed manually. The standard Westergren method was used for the
measurement of erythrocyte sedimentation rate. Chest and
abdominal plain x-rays, an ECG, and a fecal occult blood test were
optionally ordered if necessary. Microscopic examination of a
peripheral blood smear was performed in samples with any abnormality in
complete blood count or qualitative abnormalities detected by the
analyzer.
Diagnoses were established according to the reference values that were
adopted in the hospitals in which this study was carried out, with the
exception of hypercholesterolemia. Although the total cholesterol
concentration is 3.50–5.96 mmol/L (135–230 mg/dL) in 95% of healthy
individuals in Japan, its "normal" upper limit is placed at 5.70
mmol/L (220 mg/dL) in many hospitals in this country according to the
clinical guideline issued by the Japan Atherosclerosis Society, which
emphasizes on the lower value of cholesterol from the standpoint of
disease prevention. Suspected diagnosis for diabetes mellitus was made
by a positive glucose in dipstick urinalysis in combination with >7.77
mmol/L (140 mg/dL) in a random serum glucose value. A renal/urinary
tract disease was suspected by two or more strongly positive reactions
in urinalysis (at least protein and occult blood) or obvious
abnormalities in a patient’s urine sediment with or without increased
serum creatinine or urea nitrogen.
Clinical efficiency, costs, and cost-effectiveness
Because of a lack of availability of cost data at the National
Defense Medical College Hospital,
costs3
were calculated by considering all expenditures required to
obtain test results at the Kawasaki Medical School Hospital (Kurashiki,
Japan), which is a tertiary hospital similar to the National Defense
Medical College Hospital with respect to size, geographic location, and
surrounding population distribution. Costs included costs for test
reagents and analyzer operation, equipment amortization, and personnel
expenses for medical technologists. Indirect costs were excluded.
The clinical efficiency of the ELT is expressed as the number of
additional, occult diseases per patient in each disease category. The
economic efficiency of the ELT is defined as the cost required per
occult disease detected, and cost-effectiveness was determined as
incremental cost for tests added to the ELT(1) baseline panel per an
incremental occult disease uncovered by the added tests
(
cost/occult disease).
Reconstructed panels and simulated cost-effectiveness of new panels
The test package performed for 540 new outpatients included all
components of the ELT(1) panel. We modified the cumulated database to
contain patients’ chief complaints, TIDs, and test results of the
ELT(1) items alone but not to include initial clinical diagnoses
obtained from interpretation of all test items actually performed, and
then reestablished the initial diagnosis with results of the ELT(1)
components alone, simultaneously assigning additional, occult diseases
based on the ELT(1) in individual patients. The results were compared
with those obtained from test components corresponding to the ELT(2).
We further extended the study to pursue a test combination that can
provide the maximal clinical efficiency at a minimal cost increment,
analyzing occult diseases detected and costs required after certain
ELT(2)-specific test components were added to the ELT(1) basic panel.
If patients were asymptomatic and had no abnormal findings on physical
examination, additional diagnoses for diseases such as hyperlipidemia,
liver dysfunction, hyperuricemia, or diabetes mellitus could not be
established by the ELT(1) alone because of limited test items for
diagnostic evaluation of these diseases.
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Results
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Clinical and economic efficiency of the ELT panels for occult
disease finding
History and physical examination alone generated 633 effective
TIDs among 540 patients (2). Application of the ELT(2)
produced 692 primary initial clinical diagnoses corresponding to
patients’ illness and 276 additional diagnoses of occult disease or
abnormal health status, the latter being uncovered as a result of the
disease screening effect of the panel. As shown in Table 2
, the most frequent additional, occult disease was
hyperlipidemia (n = 100), followed by liver dysfunction (n =
53), hematological disease or abnormality (n = 33), and suspected
renal/urinary tract disease (n = 33 cases).
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Table 2. Asymptomatic, occult diseases and abnormal health status
detected by the ELT panels among 540 new
outpatients.
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The clinical efficiency of the ELT(2) extensive panel was 0.51 occult
disease/patient at a cost of ¥4104/occult disease for the overall
patient population (Table 3
) and varied depending on the TID category. The clinical
efficiency of the ELT(2) was 1.1–0.40 occult disease/patient, and the
cost required per occult disease detected was ¥1968–5524/occult
disease. Renal/urinary tract disease, cardiovascular disease, and
respiratory disease groups demonstrated higher clinical and economic
efficiency (1.1, 0.94, and 0.88 occult disease/patient at costs of
¥1968, ¥2879, and ¥3141/occult disease, respectively). The ELT(1)
baseline panel, which should be applied to every new patient, uncovered
only 79 cases with occult diseases or abnormal health status. Compared
with the ELT(2), there were remarkable decreases in clinical and
economic efficiency with the ELT(1): 0.15 occult disease/patient at a
cost of ¥6289/occult disease for the overall patient
population. The best cost-effectiveness (cost/occult
disease) of the ELT(2) for occult disease detection was for the
renal/urinary tract disease group (¥1521) followed by the
neurological disease (¥2251) and respiratory disease (¥2402 per
incremental occult disease) groups, although the case numbers were
small in these three disease categories. The cost-effectiveness of the
ELT(2) was ¥3228 per incremental occult disease for the overall
patient population.
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Table 3. Clinical and economic efficiency of the ELT panels for
occult disease finding among 540 new outpatients.
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Panel components contributing to occult disease finding
The frequencies of test items contributing to the detection of
additional, occult diseases are shown in Fig. 1
. In total, 511 tests detected 276 cases of occult disease or
silent abnormal health status. Basic diagnostic tests constituting the
ELT(1) made up only 22% of the total tests contributing to occult
disease detection. This low frequency corresponded to the poor clinical
and economic efficiency of the ELT(1) for occult disease finding (Table 3
). Reflecting the prevalence of the occult diseases in our patient
population (Table 2
), total cholesterol was the test that most
frequently contributed to the detection of an occult disease
(hyperlipidemia), followed by alanine aminotransferase (ALT) for liver
dysfunction and cholinesterase for possible fatty liver in patients
with increased liver transaminases. At the initial clinical evaluation,
it was difficult to diagnose hyperlipidemia with the triglyceride value
alone because of its large fluctuations related to postprandial status.
The frequencies of chest x-rays and ECGs contributing to the detection
of unforeseen, significant diseases were very low, despite the higher
costs for both tests (¥877 and ¥699 per test, respectively).
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Figure 1. The ELT components and their frequency of contribution to
occult disease finding.
Filled columns indicate contributions of the ELT(1)
component tests to occult disease finding; hatched
columns indicate those of the ELT(2)-specific test items. In
total, 511 tests contributed to discovery of 276 additional, occult
diseases among 540 new outpatients. WBC, white blood
cell count; A/G ratio, albumin/globulin ratio;
RBC indices, red blood cell indices; ESR,
erythrocyte sedimentation rate; GGT,
 -glutamyltransferase; AST, aspartate
aminotransferase; LD, lactate dehydrogenase;
ALP, alkaline phosphatase; LDC, leukocyte
differential count; BUN, serum urea nitrogen. *
indicates optionally ordered tests.
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Simulated cost-effectiveness of reconstructed test panels
Considering the individual test items that largely contributed to
the discovery of additional, silent diseases, we redesigned new panels
based on the ELT(1), the most fundamental test package, adding some
ELT(2) test items, and then analyzed the cost-effectiveness of the new
panels to seek more efficient test combinations for occult disease
finding. As shown in Table 4
, the addition of only four automated analyzer-based chemistry
tests (total cholesterol, ALT, glucose, and uric acid) to the ELT(1)
test components produced remarkably improved clinical and economic
efficiency (0.41 occult disease/patient and ¥2372/occult disease,
respectively) at a cost-effectiveness of ¥177 per incremental occult
disease (Table 4
, panel A). Addition of more of the ELT(2) test items
to the ELT(1) slightly increased clinical efficiency but decreased
cost-effectiveness (Table 4
, panels B and C). Optional test
items (chest and abdominal x-rays, ECG, and fecal occult blood test)
scarcely contributed to the improvement in clinical efficiency, but
rather increasingly worsened cost-effectiveness for occult disease
finding [compare cost-effectiveness of panel C with that of the ELT(2)
in Table 4
].
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Table 4. Cost-effectiveness of redesigned panels of common
diagnostic tests for occult disease finding among 540 new outpatients
in primary care medicine.
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Discussion
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The present study is a counterpart of our previous study, which
analyzed cost-effectiveness of the ELT panels for clinical evaluation
of patients’ presenting illness (2). In our earlier study,
however, we did not refer to the case-finding efficiency of the panels.
Although biochemical profile testing for the purpose of case-finding
among asymptomatic adults is not currently recommended in general
(11), it seems to be acceptable to apply some selective
tests, which can uncover clinically silent but significant diseases
such as hypercholesterolemia and diabetes, to certain patients who
appear to have risks for coronary heart disease or stroke. There is a
higher prevalence of hepatitis virus-induced chronic liver diseases and
subsequent hepatocellular carcinoma in Japan than in Western countries,
prompting the need to find asymptomatic patients with liver dysfunction
(12). Recent advances in medical technology allow
inexpensive testing of total cholesterol, serum glucose, and other
automated multichannel analyzer-based chemistry tests. The issue is not
the expense of testing itself, but what is required is persuasive,
strong evidence based on cost-effectiveness evaluations for the
validity of a screening program.
As shown in Table 3
, there is a substantial disparity in the
cost-effectiveness of the ELT panels for additional, occult disease
detection. A higher prevalence of occult diseases and the favorable
cost-effectiveness indicators of the ELT(2) panel were demonstrated in
cardiovascular, renal/urinary tract, and respiratory disease groups,
although the small numbers of patients do not allow a conclusive
statement in the latter two disease categories. Except for these three
disease groups, clinical efficiency and economic consequence of the
ELT(2) were poor among our patients. This corresponds to experts’
opinion that the performance of a general battery of biochemical tests
is not recommended for screening of asymptomatic adults
(11). Patients with cardiovascular TIDs seem to be the only
group for whom the extensive test panels, rather than the basic one
[the ELT(1)], are indicated for occult disease detection on the basis
of cost-effectiveness, and active efforts to screen for diseases such
as hypercholesterolemia and diabetes, which are known risk factors for
atherosclerosis, should at least be directed toward this patient group.
In the case of cholesterol screening, clinical guidelines issued by the
National Cholesterol Education Program (13) and by the
American College of Physicians (14)(15) state
that all adults older than 20 years (the former) or primarily
middle-aged men (the latter) with hypercholesterolemia be identified,
educated, and treated. In addition, recent clinical trials showed that
cholesterol reduction confers survival benefits in patients with
symptomatic coronary heart disease (16)(17)(18) and lowers the
incidence of cardiovascular morbidity and mortality in patients without
coronary symptoms (19)(20). Cholesterol
reduction decreases the incidence of stroke as well (21).
Likewise, the CDC Diabetes Cost-Effectiveness Study Group
recently demonstrated that early diagnosis and treatment of type 2,
non-insulin-dependent diabetes through opportunistic screening may
reduce the lifetime incidence of major microvascular complications,
producing gains in both life-years and quality-adjusted life-years with
an acceptable cost-effectiveness for the US healthcare system
(22). These recommendations and results obtained from the
clinical trials might support physicians’ efforts for screening of
significant occult diseases for which patient education, management,
and early treatment are effective in preventing disease progression,
ultimately providing cost-effective medical care. The validity of
proposed screening programs should be endorsed by a broad range of
cost-effectiveness analyses.
Comparison of the ELT(1) with the ELT(2) demonstrated limited utility
of the former baseline panel in the aspect of clinical and economic
efficiency for occult disease finding in all disease categories (0.15
occult disease/patient at a cost of ¥6289/occult disease). Although
application of the entire ELT(2) panel to patients considerably
improved the overall clinical efficiency (up to 0.51 in occult
disease/patient tested), cost remained high [¥4104 (~$40
US)/occult disease; Table 3
]. The poor cost-effectiveness
(cost/occult disease) of the ELT(2) vs the ELT(1) baseline panel
prompted us to seek more efficient test combinations, adding one or
more ELT(2)-specific test items that highly contributed to occult
disease detection to the ELT(1) panel. As anticipated from Fig. 1
, the
cost-effectiveness indicators were markedly improved by the addition of
only four automated analyzer-based chemistry tests (total cholesterol,
ALT, glucose, and uric acid) at an excellent cost-effectiveness of
¥177 per incremental occult disease (Table 4
, panel A). Addition of
more of the ELT(2) test components to this redesigned panel minimally
increased clinical efficiency and decreased cost-effectiveness. In
particular, plain x-rays and ECGs showed little utility for the
discovery of occult diseases in our patients because of an extremely
low prevalence of clinically silent but significant organic diseases
and higher costs for performing these tests. This finding entirely
supports the recommendations from the Medical Necessity Project of the
American College of Physicians for common diagnostic test utilization,
which indicate a limited usefulness of chest x-rays and ECGs as routine
screening diagnostic procedures even for a baseline evaluation of
preoperative patients or at the time of hospital admission
(7)(23).
Our previous studies recommended the utilization of selective ELT
panels for selected patient groups such as those with
liver/pancreatobiliary, metabolic/endocrine, or cardiovascular diseases
(2), or those with infection/inflammation-related,
renal/urinary tract, or lassitude/exhaustive symptoms (24).
In addition to the utility of the ELT for the clinical evaluation of
the illness of which a patient complains, silent diseases can be
simultaneously screened with the use of this panel test system. Indeed,
our present study demonstrated that the addition of total cholesterol,
ALT, and random serum glucose to the ELT(1) enabled the detection of
100, 53, and 13 cases of hypercholesterolemia, liver dysfunction, and
suspected diabetes mellitus, respectively, among 540 new outpatients in
our institutes with acceptable cost-effectiveness. Incorporating these
results with our previous studies relating to the cost-effectiveness of
the ELT panels, clinical evaluation of a patient’s illness by the
selective use of this panel system could be accompanied by
opportunistic screening of significant occult diseases. Thus, each
selective panel for selected patients could include the ELT(2)-specific
chemistry test items that largely contribute to the discovery of the
clinically silent but significant diseases shown above.
In conclusion, although the JSCP panel test system has supplemental
utility for the opportunistic screening of some significant, occult
diseases, universal utilization of the full panel [the ELT(2)] is not
supported by the cost-effectiveness found in our studies. Simultaneous
screening of specific occult disease(s), however, might be valid and
further improve the clinical and economic efficiency of the panel test
system when the panels are given to selected patients for clinical
evaluation of their illnesses. Our cost-effectiveness analysis
demonstrated specific screening test items that could be added to each
selective panel for certain patient groups. The validity of enforcing
such screening tests alone to all or only risky individuals is
uncertain in our current studies.
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Acknowledgments
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This study was supported in part by grants from the Clinical
Pathology Research Foundation of Japan and from the Pfizer Health
Research Foundation. We thank Yasumasa Kajihara, Reishi Izumi,
Katsunori Koguchi, Mitsugi Okura, and Kuniki Takamatsu at Kawasaki
Medical School, Kurashiki, Japan for providing cost data for x-ray
tests and laboratory tests. We also thank Nobuo Kugai and Hirokazu
Matsuta at the National Defense Medical College, Tokorozawa, Japan for
assistance in collecting clinical data.
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Footnotes
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1 Nonstandard abbreviations: JSCP, Japan Society of Clinical Pathology; ELT, Essential Laboratory Tests; ECG, electrocardiogram; TID, tentative initial diagnosis; CRP, C-reactive protein; and ALT, alanine aminotransferase. 
2 Definitions for descriptions specifically used: clinical efficiency, the number of additional occult diseases detected per patient (occult diseases/patient); economic efficiency, the cost required per occult disease detected (cost/occult disease); cost-effectiveness, incremental cost for tests added to the ELT(1) baseline panel per incremental case of occult disease discovered (cost/occult disease).
3 Cost (¥) can be converted to US dollars at a rate of US $1.00 = ¥105.00 on February 1, 2000.
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The following articles in journals at HighWire Press have cited this article:
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Y. Takemura, H. Ishida, Y. Inoue, and J. R. Beck
Yield and Cost of Individual Common Diagnostic Tests in New Primary Care Outpatients in Japan
Clin. Chem.,
January 1, 2002;
48(1):
42 - 54.
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Abstract
Introduction
