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CLINICAL TRIALS AND OBSERVATIONS
Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes
theorem approach
Alberto Tosetto,1 Giancarlo Castaman,1 and Francesco Rodeghiero1
1Hematology
Department, San Bortolo Hospital, Vicenza, Italy
The diagnosis of type 1 von Willebrand
disease (VWD) is based on the presence of
bleeding symptoms, reduced von Willebrand factor (VWF) levels, and autosomal
inheritance of the phenotype. To better appreciate the contribution of clinical and laboratory data to the final diagnosis of VWD, we
computed the likelihoods of having VWD as
a function of the bleeding score (LRscore), of
VWF level (LRVWF), and of number of firstdegree family members with reduced VWF
levels (LRfamily). The 3 likelihoods were therefore combined using the Bayes theorem,
giving the final probability (odds) of having
VWD. LRfamily and LRVWF were the 2 factors
mostly influencing the final probability of
having VWD. Data from the present study
provide an evidence-based description of
the minimal criteria for the diagnosis of type
1 VWD. As an example, presence of VWF
levels lower than 40 IU/dL in at least 2 family
members (including the proband) and a
bleeding score of at least 1 were found to be
required for a final odd of VWD higher than
2.0 (false-positive rate less than one-half).
Validation of this approach and of its clinical
utility is, however, required by analysis in
other cohorts of well-characterized type 1
VWD patients. (Blood. 2008;111:3998-4003)
© 2008 by The American Society of Hematology
Introduction
present the development of a Bayesian model for the diagnosis
of VWD as a tool for evidence-based diagnostic criteria.
The last decade has witnessed an increasing interest in the
diagnosis of von Willebrand disease (VWD). Much of this
interest stems from the high prevalence of VWD in the
population, ranging from 0.1% to 1%,1,2 making VWD the most
frequent inherited bleeding disorder, and therefore its diagnosis
relevant for a clinician. The most common variant of VWD is
represented by type 1 VWD, a quantitative deficiency of von
Willebrand factor (VWF) without overt abnormalities of the
circulating molecule, as detected by sensitive immunoelectrophoretic techniques.3,4 Type 1 VWD is transmitted as an
autosomal dominant (heterozygous) disease, and a substantial
overlap of both clinical and laboratory phenotype is usually
present between VWD patients and healthy subjects, particularly in mild cases of VWD.5 In view of the difficulties for an
appropriate diagnosis of type 1 VWD, provisional criteria have
been recently formulated.6 These criteria rest on the presence of
bleeding symptoms and reduced VWF levels in the patient,
together with an autosomal inheritance of the phenotype.
Unfortunately, these provisional criteria are essentially based on
experts’ consensus rather than on evidence.
A different approach to the diagnosis of VWD may be to
estimate the final probability of type 1 VWD based on the
combination of the likelihood of having VWD as a function of
bleeding severity, VWF levels, and first-degree relatives sharing
a deficiency of VWF. This approach, based on the well-known
Bayes theorem, allows the estimation of the probability (odds)
of having VWD as a function of an individual patient phenotype,
including inheritance.7 Such an approach has become feasible
since the recent availability of large, multicenter studies on
different cohorts of type 1 VWD patients.8-10 In this paper, we
According to the Bayes theorem, the odds of a disease could be computed as
the a priori probability of a disease multiplied by the likelihood ratio (LR)
supporting or opposing that diagnosis. LRs are essentially the ratio between
the probabilities of being affected or not for any specific phenotype, such as
a particular clinical finding or a specific value of a laboratory test. Thus, in
the Bayes theorem, the baseline prior probability of a disease (eg, the
prevalence of VWD) is multiplied by the LR given by a clinical or
laboratory finding to obtain a posterior probability of that disease in the
studied subject. In turn, this latter probability could be further refined by
further multiplication by the LR given by another observation (thus
posterior probabilities could always be used as better priors probabilities
for another LR, provided that all LRs are independent and unbiased11).
LRs could be considered as independent and unbiased when their estimates
are obtained from different datasets (independent) and their effect is not
influenced by other LRs (unbiased). Therefore, under the hypothesis of
a low disease prevalence, the model could be written as
oddsdisease ⫽ prevalence ⫻ LR1 ⫻ LR2 ⫻ . . . LRn, where LRn is the likelihood
ratio of having the disease for 1 to n different clinical or laboratory tests.7 Thus,
computing the final odds of VWD requires appreciation of VWD prevalence and
of the LR of having VWD for each involved test as a function of the individual
phenotype. For type 1 VWD, we computed the odds of being VWD as a function
of bleeding symptoms (LRscore), plasma VWF levels (LRVWF), and number of
first-degree family members having reduced VWF levels (LRfamily). The choice
of these 3 LRs (LRscore, LRVWF, and LRfamily) was consequent to the definition of
VWD as an inherited bleeding disorder with reduced VWF.6
Submitted August 8, 2007; accepted December 21, 2007. Prepublished online
as Blood First Edition paper, January 10, 2008; DOI 10.1182/blood-2007-08105940.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
An Inside Blood analysis of this article appears at the front of this issue.
© 2008 by The American Society of Hematology
3998
Methods
Development of the model
BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
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BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
Prevalence of VWD was conservatively estimated to be 0.1% in the
general population.1,2,12
Likelihood ratios of VWD as a function of bleeding severity
(LRscore)
BAYESIAN-BASED DIAGNOSIS OF TYPE 1 VWD
Table 1. Probability of having low VWF levels in parents and
offspring given presence (VWD families) or absence (healthy
families) of a disease gene transmitted as an autosomal dominant
trait
Probability of low VWF
Healthy families
We evaluated data from an international, multicenter study on type 1 VWD
patients (hereafter referred as IMS-VWD).8 In the IMS-VWD, 42 obligatory
carriers of type 1 VWD were selected on the basis of inheritance, subjects being
considered as obligatory carriers (OCs) if they had at least an affected offspring
and at least another affected first-degree relative (either father/mother or
brother/sister). Thus, the IMS-VWD study selected VWD patients independently from their bleeding history and from their plasma VWF level;
therefore, LRscore derived from the IMS-VWD study could be considered as
independent from LRVWF. Two hundred fifteen subjects without history of
bleeding disease were considered as a control group, as previously
described.8 Using a publicly available standardized questionnaire,13 bleeding symptoms were collected through a physician-driven interview and
summarized in a bleeding score (BS).8,14 The BS is generated by summing
the severity of all bleeding symptoms reported by a subject, and graded
according to an arbitrary scale ranging from 0 (complete absence of
symptom) to 3. Grade 1 was given when a patient reported presence of
bleeding, grade 2 if the symptom required evaluation by a physician but no
active intervention, and grade 3 if there was some kind of intervention by
the physician. Based on the original study dataset, we computed for the
present study the LR of VWD as the ratio between the percentages of type 1
VWD OCs versus control subjects with that particular BS value. Computations of LRs and their 95% confidence intervals were carried out according
to Pepe15 using the Stata “diagt” procedure (Stata Statistical Software:
Release 10.0; StataCorp, College Station, TX).
Likelihood ratios of VWD as a function of VWF level (LRVWF)
We used data from the MCMDM-1VWD study, a multicenter European study
that enrolled 154 families with von Willebrand disease and 1166 healthy
controls10 Likelihood ratios in type 1 VWD have been recently reported,16 and
were computed for those subjects that in addition to having been diagnosed
historically as VWD by the enrolling center (either index case or affected family
member) belonged to a family showing clear linkage of the VWD phenotype
with the VWF locus (totaling 204 subjects belonging to 64 families). This latter
requirement allowed to base the computation of LRVWF on those patients for
whom the level of measured VWF was of less importance for their diagnosis.
Furthermore, families enrolled in the MCMDM-1VWD study are different from
those enrolled in the IMS-VWD study. Thus, computation of both LRscore and
LRVWF could be considered as unbiased (ie, LRscore is not based on diagnoses
contingent on bleeding, and LRVWF is largely not based on the VWF level actually
measured in the MCMDM-1VWD study) and independent (because they are
based on independent datasets). Therefore, LRscore and LRVWF could be used
multiplicatively for the calculation of the final probability of having VWD. It
should be noted that the LRVWF does assume that no factor potentially influencing
VWF levels (eg, pregnancy, inflammatory states) is present in the considered
proband. Sampling and computation of LRVWF should be withheld until resolution of the influencing conditions when present.
Likelihood ratios of VWD as a function of family members with
reduced VWF levels (LRfamily)
Within a family of size s, the probability of finding n family members with
reduced VWF levels (n possibly ranging from 0 to s, 0 ⱕ n ⱕ s) depends on
the presence of the disease gene within the family and on the sensitivity and
specificity of the test, these latter being the probabilities of finding an
abnormal VWF level conditional to the presence or absence of an abnormal
disease gene, respectively. On the basis of a previous study, we assumed a
sensitivity of 0.8 and a specificity of 0.975 for VWF measurement,
corresponding to the sensitivity and specificity given by the 2.5 percentile
reference limit.16 The probability of having a low VWF conditional of
belonging to a healthy or VWD family is reported in Table 1, under the
hypothesis of an autosomal disease with low frequency in the population
(for this reason, in this model we assumed that only one parent could be a
3999
VWD families
First generation, parents
1⫺Spec ⫽ 0.025
Sens if carrier ⫽ 0.80;
Second generation, offspring
1⫺Spec ⫽ 0.025
0.5⫻Sens if carrier;
1⫺Spec if not carrier ⫽ 0.025
0.5⫻(1⫺Spec) if not carrier
0.5⫻Sens ⫹ 0.5⫻(1⫺Spec) ⫽
Overall
0.5⫻(1⫹Sens⫺Spec) ⫽ 0.4125
carrier of VWD).17 In healthy families, the final probabilities of finding n
subjects with reduced VWF (with probability ⫽ 1-Specificity) from s are
computed using the binomial distribution. In VWD families, the probability
of finding nparents (0 ⱕ nparents ⱕ 2) with reduced VWF should be summed
with the probability of finding nsibs (0 ⱕ nsibs ⱕ s-2) with reduced VWF, this
latter quantity being computed using the binomial distribution with
probability 0.5 ⫻ (1 ⫹ sensitivity ⫺ specificity). LRfamily is finally computed for each value of n as the ratio of the probabilities obtained in VWD
and in healthy families. Likelihood ratios derived by this theoretic model
completely predicted the results obtained by a computer simulation using
the Stata “simuped” procedure (Stata Statistical Software). Since LRfamily
was computed following the theoretic assumption of an autosomal
dominant model, LRfamily could be considered as valid and independent from LRVWF and LRscore and could therefore also be used as the third
LR in our model.
The study protocols of the IMS-VWD study and of the MCMDM-1VWD
study were submitted and approved by local Internal Review Boards, according
to the rules present in each country of the participating centers (see refs 8 and 9 for
a list of participating centers). Informed signed consent was obtained from each
patient in accordance with the Declaration of Helsinki.
Results
Likelihood ratios of VWD as a function of bleeding severity
The likelihoods of having VWD as a function of the BS in
obligatory carriers of VWD are reported in Table 2. Bleeding
scores equal or lower than 2 were all associated with an LR lower
than 1, hence lowering the final probabilities of being a VWD
patient, whereas a substantial increase in the final probability was
observed for BS equal or greater than 5.
Likelihood ratios of VWD as a function of family members with
reduced VWF levels (LRfamily)
As expected, the likelihood of VWD increased almost exponentially as the number of family members with reduced VWF
Table 2. Likelihood ratios for VWD at different levels of bleeding
score
Bleeding
score
No. of investigated
subjects
OCs
Controls
Likelihood ratio (95% CI)
0
3
158
0.097 (0.03-0.29)
1
2
20
0.51 (0.12-2.11)
2
2
14
0.73 (0.17-3.10)
3
4
9
2.28 (0.73-7.05)
4
6
11
2.79 (1.09-7.13)
5
5
2
12.8 (2.57-63.8)
6
4
1
20.5 (2.35-179)
20
1
102 (14.1-742)
6 or more
OC indicates obligatory carrier.
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4000
BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
TOSETTO et al
Table 3. Likelihood ratios for VWD in a nuclear family, based on the
number of siblings in the family and on the number of family
members with reduced VWF levels (lower than the 2.5 percentile)
Likelihood ratio
No. of siblings in the family
No. of family members
with reduced VWF*
1
2
1
7.5
4.16
112
3
2.4
2
165
67.9
3
462
2115
1617
4
—
7623
28833
5
—
—
125779
— indicates not applicable.
*Including propositus.
increased within a family (Table 3; Figure 1). Although the actual
LR varied as a function of the family size, the slope and shape of
the likelihood profiles was remarkably similar (Figure 1). As a
general rule, however, a family without any family member with
VWF levels lower than the 2.5 percentile (corresponding to a
VWF:Ag or VWF:RCo lower than 47 IU/dL in a large cohort of
healthy subjects16) is highly unlikely to have VWD. On the
contrary, finding 2 members with reduced VWF levels strongly
suggests the presence of VWD. It should be noted that LRfamily is
computed either including or excluding the proband depending on
his/her VWF values. For instance, if the proband and another
sibling have VWF levels lower than 40 IU/dL, then the proband
will get the same LRfamily of a proband with normal VWF but with
2 other siblings with VWF lower than 40 IU/dL. In subjects
without family data available (ie, with information coming only
from the proband), LRfamily is assumed to be 16.5 (0.4125,
probability of low VWF in VWD family, divided by 0.025,
probability of low VWF in a healthy family, Table 1) if the proband
has reduced VWF; LRfamily is assumed to be 0.60 (0.5875,
probability of normal VWF in VWD family, divided by 0.975,
probability of low VWF in a healthy family, Table 1) otherwise. In
families with incomplete familial investigation, computation of
LRfamily could be derived assuming as the family size the total
number of subjects actually investigated.
Final odds of VWD
Tables 4, 5, and 6 report, respectively, the final odds of VWD in
subjects without a family investigation available and in subjects
with 4 and 5 investigated family members.
Discussion
Although type 1 VWD is the most prevalent hemorrhagic disorder,2
its diagnosis still remains a clinical challenge.5,18 Provisional
diagnostic criteria have been published, based on the presence of
bleeding symptoms, reduced VWF levels, and inheritance of the
phenotype within the family.6,19 Unfortunately, the contribution of
each of these 3 factors to the final diagnosis is unknown, as is
unknown the proportion of truly affected patients among all those
subjects fulfilling the criteria (ie, the positive predictive value of
the proposed criteria). Furthermore, current proposed criteria do
not exploit all the clinically available information, since data are
dichotomized into normal/abnormal values. For instance, an individual with borderline VWF levels (eg, lower than 40 IU/dL)
would be considered abnormal just as an individual with severely
reduced VWF (eg, lower than 20 IU/dL), even if the latter subject is
obviously more likely to have VWD than the former one.
In this study, we aimed at appreciating the different contribution
of bleeding symptoms, reduced VWF levels, and inheritance of the
phenotype to the diagnosis of type 1 VWD and to quantitatively
estimate the diagnostic accuracy of a VWD diagnosis based on the
clinical and laboratory phenotype. For this purpose, we combined
clinical and laboratory data using the Bayes theorem, an approach
that has never been used before for the diagnosis of bleeding
disorders. This methodology has the benefits of exploiting both
qualitative and quantitative information (eg, VWF levels) and of
providing the clinician the final probability (odds) of having VWD
against being healthy. For instance, final odds of 2.0 means that
every 3 evaluated subjects, 2 will have VWD and 1 will not (or a
2/3 ⫽ 66.6% positive predictive value); final odds of 10.0 means a
10:1 ratio of true-false positives (or 10/11 ⫽ 90.9% positive
predictive value). Odds could be readily converted into probabilities of disease with the formula probability ⫽ odds/(odds ⫹ 1).
Thus, the clinician may have an immediate perception of the degree
of certainty of the diagnosis, with final odds lower than 2.0 possibly
having a high risk of misdiagnosis (since probability of VWD in
this case would be 2/3 ⫽ 66%. In fact, in subjects with final odds
lower than 2.0, reduction of circulating VWF may be better
considered a risk factor for bleeding rather than causative of a
disease, as has already been proposed.5 Application of the Bayes
theorem to VWD was made possible by the recent availability of
data coming from studies on large cohorts of VWD (the IMS-VWD
Figure 1. Log-likelihood ratio of VWD in nuclear
families. The vertical axis shows the likelihood ratio (in
a log scale), as a function of the number of affected
family members in the family.
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BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
BAYESIAN-BASED DIAGNOSIS OF TYPE 1 VWD
4001
Table 4. Final odds of VWD based on the combination of LR from bleeding score and VWF:Ag level
Bleeding score
VWF:Ag, IU/dL
0
1
2
3
4
5
6
6 or more
Less than 20
0.59
3.14
4.50
14.06
17.21
78.98
126.50
629.44
20 to 40
0.15
0.80
1.14
3.57
4.37
20.08
32.16
160.05
40 to 47
0.00
0.01
0.02
0.07
0.08
0.38
0.61
3.06
47 to 60
0.00
0.00
0.00
0.00
0.00
0.01
0.02
0.11
60 or more
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.01
No family investigation was available.
Final odds from 2.0 to 10.0 in italic; final odds higher than 10 in bold. Odds could be converted into probabilities of disease with the formula probability⫽odds/(odds⫹1).
and MCMDM-1VWD studies).9,10,16 Since the IMS-VWD and
MCMDM-1VWD enrolled different patient populations and used
different selection criteria, combination of data from these 2 studies
was possible, thus avoiding as much as possible circular reasoning
for a disease without an independent diagnostic gold standard. The
IMS-VWD was used to compute LR for the BS since in this study
patients were selected independently from the presence of bleeding
symptoms, therefore allowing unbiased estimation of LRscore.8 As a
consequence, the questionnaire and the BS used by the IMS-VWD
were used for this study.14 We used LRVWF recently reported in the
MCMDM-1VWD study since VWF was measured in a core
laboratory from a large cohort of patients and controls.10 VWF:Ag
was chosen as the reference method instead of VWF:RCo, given its
better intralaboratory and interlaboratory reproducibility.16,20 Finally, we conservatively assumed a low prevalence of VWD (0.1%
or 1 per 1000) in the population, since it possibly better reflects the
prevalence of VWD as an autosomal dominant disease, with both
proband and family members having VWF levels lower than the
2.5 percentile, as requested in our model. Given the properties of
the Bayes theorem, however, changing the prevalence to 1 per 100
or 1 per 10 000 would mean multiply (or divide) by 10 the
probabilities reported in Tables 4, 5, and 6.
The study demonstrates first that the most important clue to the
diagnosis of VWD is inheritance of the phenotype, followed by
reduced VWF and bleeding symptoms in the proband. This could
be easily appreciated by the very steep increase of LRfamily (and
hence, of final odds) as a function of the number of family members
found to have reduced VWF. On the contrary, the absolute
contribution of LRscore and LRVWF to the final odds is much lower. In
subjects without family data available, final odds of VWD higher
than 2.0 are obtained only for very low VWF values together with
very high BS (Table 4).
Second, the study shows that no single clinical or laboratory
criterion reaches final odds higher than 2.0 (apart from the very
unlikely situation of a family where almost everyone has reduced
VWF levels). This study therefore confirms that at least a clinical
and a laboratory positive finding need to be present for VWD
diagnosis. For instance, having VWF levels lower than 20 IU/dL
together with another family member with reduced VWF is highly
likely to be associated with VWD, since combination of these 2
criteria results in final odds of at least 4.06 (Table 5). In patients
with less severe reduction of VWF, however, the contribution of
bleeding symptoms is always required to reach a sensible diagnosis. Hence, in the more frequent case of patients with VWF levels
ranging from 20 to 40 IU/dL, a bleeding score of at least 1 together
with another family member with reduced VWF are required for a
final odds of at least 5.4 (Table 5).
Table 5. Final odds of VWF based on the combination of LR from bleeding score, VWF: Ag level, and number of family members with VWF
lower than the 2.5 percentile
Bleeding score
VWF:Ag, IU/dL
0
1
2
Less than 20
0.15
0.79
1.14
20 to 40
0.04
0.20
0.29
40 to 60
0.00
0.00
0.01
60 or more
0.00
0.00
3
4
5
6
6 or more
3.55
4.34
19.91
31.89
158.70
0.90
1.10
5.06
8.11
40.35
0.02
0.02
0.10
0.16
0.77
0.00
0.00
0.00
0.01
0.01
0.04
1 family member with VWF lower than 2.5 pctl*
2 family members with VWF lower than 2.5 pctl*
Less than 20
4.06
21.36
30.58
95.50
116.87
536.17
858.70
4272.58
20 to 40
1.03
5.43
7.78
24.28
29.72
136.34
218.35
1086.42
40 to 60
0.02
0.10
0.15
0.46
0.57
2.61
4.18
20.79
60 or more
0.00
0.01
0.01
0.03
0.03
0.14
0.23
1.14
Less than 20
76.73
403.42
577.44
1803.50
2206.92
10124.93
16215.71
80683.02
20 to 40
19.51
102.58
146.83
458.59
561.17
2574.55
4123.30
20515.92
40 to 60
0.37
1.96
2.81
8.78
10.74
49.27
78.91
392.63
60 or more
0.02
0.11
0.15
0.48
0.59
2.71
4.34
21.57
3 family members with VWF lower than 2.5 pctl*
4 family members with VWF lower than 2.5 pctl*
Less than 20
276.55
1454.01
2081.23
6500.28
7954.30
36492.83
58445.54
290802.20
20 to 40
70.32
369.72
529.21
1652.88
2022.60
9279.33
14861.42
73944.62
40 to 60
1.35
7.08
10.13
31.63
38.71
177.59
284.41
1415.13
60 or more
0.07
0.39
0.56
1.74
2.13
9.76
15.63
77.75
Final odds from 2.0 to 10.0 in italic; final odds higher than 10 in bold. Odds could be converted into probabilities of disease with the formula probability⫽odds/(odds⫹1).
*Total family size ⫽ 4. Proband included.
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BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
TOSETTO et al
Table 6. Final odds of VWF based on the combination of LR from bleeding score VWF: Ag level and number of family members with VWF
lower than the 2.5 percentile
Bleeding score
VWF:Ag, IU/dL
0
1
2
3
4
5
6
6 or more
1 family member with VWF lower than 2.5 pctl *
Less than 20
0.09
0.45
0.65
2.02
2.47
11.35
18.17
90.41
20 to 40
0.02
0.11
0.16
0.51
0.63
2.88
4.62
22.99
40 to 60
0.00
0.00
0.00
0.01
0.01
0.06
0.09
0.44
60 or more
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.02
Less than 20
2.46
12.96
18.54
57.92
70.87
325.15
520.74
2591.01
20 to 40
0.63
3.29
4.72
14.73
18.02
82.68
132.41
658.84
40 to 60
0.01
0.06
0.09
0.28
0.34
1.58
2.53
12.61
60 or more
0.00
0.00
0.00
0.02
0.02
0.09
0.14
0.69
Less than 20
58.66
308.43
441.47
1378.85
1687.27
7740.90
12397.54
61685.32
20 to 40
14.92
78.43
112.26
350.61
429.04
1968.34
3152.42
15685.22
40 to 60
0.29
1.50
2.15
6.71
8.21
37.67
60.33
300.18
60 or more
0.02
0.08
0.12
0.37
0.45
2.07
3.31
16.49
2 family members with VWF lower than 2.5 pctl*
3 family members with VWF lower than 2.5 pctl*
4 family members with VWF lower than 2.5 pctl*
Less than 20
1046.00
5499.61
7871.99
24586.48
30086.08
138029.34
221062.61
1099921.28
20 to 40
265.98
1398.43
2001.67
6251.80
7650.23
35097.83
56211.38
279685.87
40 to 60
5.09
26.76
38.31
119.65
146.41
671.69
1075.76
5352.56
60 or more
0.28
1.47
2.10
6.57
8.04
36.91
59.11
294.10
Less than 20
4563.01
23991.01
602129.23
964347.59
4798217.29
20 to 40
1160.27
6100.41
8731.96
27272.41
33372.82
153108.26
245212.45
1220081.46
40 to 60
22.21
116.75
167.11
521.93
638.68
2930.15
4692.81
23349.61
1.22
6.41
9.18
28.68
35.09
161.00
257.85
1282.95
5 family members with VWF lower than 2.5 pctl*
60 or more
34340.1
107254.27
131245.2
Final odds from 2.0 to 10.0 in italic; final odds higher than 10 in bold. Odds could be converted into probabilities of disease with the formula probability⫽odds/(odds⫹1).
*Total family size ⫽ 5. Proband included.
The results of the present study could be compared with the
provisional criteria recently published,6 classifying type 1 VWD
patients as “definite” and “possible.” Definite type 1 include
significant mucocutaneous bleeding (at least 2 symptoms or one
requiring blood transfusion, totaling a BS possibly ranging from 2
to 4), reduced VWF levels (⬎ 2 SD lower than the mean), and at
least another family member with reduced VWF. Accordingly, in a
nuclear family of 4, the final odds of VWD according to the
“definite” provisional criteria may range from 0.15 (Table 5: 2
affected, BS ⫽ 2, VWF level ⫽ 2 SD lower than the mean but
higher than 40 IU/dL) to well higher than 100 (2 affected, BS ⫽ 4,
VWF level ⫽ 20 IU/dL). Even for the “possible” category (reduced VWF level ⬎ 2 SD lower than the mean and either significant mucocutaneous bleeding or at least another family member
with reduced VWF), final odds may range from 0.02 (Table 5:
VWF level ⫽ 2 SD lower than the mean but higher than 40 IU/dL,
BS ⫽ 4, and no other affected family member) to higher than 4
(VWF level ⫽ 20 IU/dL, BS ⫽ 0, but another affected family
member). It is therefore clear that the use of the “provisional”
criteria may be very accurate in some circumstances, yielding
diagnosis with a high probability of VWD (eg, those with final odds
higher than 100) but potentially misclassifying patients in
other settings (eg, those with final odds of 0.02 are most likely
false positives).
When would this proposed approach be useful for the clinician?
It should be noted that in the MCMDM-1VWD study, very low
VWF levels are associated both with higher bleeding scores and
with presence of a disease gene. Therefore, we could expect that in
families carrying a VWD gene with a severe phenotype (VWF
lower than 20 IU/dL), very high final odds of VWD could be
generated in carriers. Thus, a quantitative approach to VWD
diagnosis adds little information in severe type 1 VWD and could
confirm only an otherwise easy diagnosis. Our approach could be
particularly useful for the clinician in 2 less clear-cut, but more
frequent, situations. First, most cases of VWD come from families
with mild reduction of VWF levels, where considerable overlap
exists even with healthy subjects. In this case, a quantitative
appreciation of the odds of being affected could be useful both for
clinical and research purposes. Second, our approach could also be
useful for the exclusion of the VWD diagnosis. For instance, a
negative bleeding history (BS less than 3, as found in healthy
subjects) is invariably associated with an LRscore lower than 1,
hence dramatically lowering the final odds of VWD. A strong
negative value could be attributed also to lack of inheritance (ie, no
family member with reduced VWF or none other than the proband)
and to VWF values higher than 60 IU/dL. As an example, our
approach could be useful for the exclusion of healthy individuals in
families with severe VWD, since in this setting finding a low BS or
intermediate VWF levels may considerably lower the high LRfamily.
Finally, it should be noticed that the results of this study rest on the
assumption that VWD is based on a clear-cut genetic model (a
monogenic, autosomal dominant disease with incomplete penetrance). Even on this simple assumption, our study suggests that
extreme caution should be used for the diagnosis of VWD in
subjects with mild reduction of VWF and, therefore, even more
conservative criteria should be used assuming a more complex
genetic background of VWD (eg, allowing for the presence of
phenocopies, epistasis, and multigenic effects). In this respect, this
study aims at providing a quantitative assessment of the magnitude
of the diagnostic uncertainties of VWD diagnosis.
Several questions remain unanswered, however, and will need
further investigation. First, it is presently difficult to establish a
cutoff for an optimal diagnosis of VWD. The appreciation of the
diagnostic sensitivity and of the unavoidable trade-offs for various
From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
BLOOD, 15 APRIL 2008 䡠 VOLUME 111, NUMBER 8
BAYESIAN-BASED DIAGNOSIS OF TYPE 1 VWD
cutoffs will necessarily require the validation against a new set of
patients independently diagnosed as having VWD. Second, it could
be postulated that higher final odds of VWD could correlate with
severity of disease and hence with bleeding risk, but this will also
require validation by large, prospective surveys on VWD patients.
Prospective surveys will also be needed to evaluate which one of
the 3 components used to compute the final odds is the stronger
predictor of the bleeding risk in VWD patients. Finally, the clinical
utility of our proposed algorithm should be tested in prospective
series of bleeding patients, without a previous diagnosis of VWD.
The study has some limitations; in particular, it is limited to the
adult population and it does not take into account variables such as
sex or age that have been previously demonstrated to be associated
with an increased BS. Thus, the results of the present study should
be applied with great caution to pediatric patients, and specific
studies in children should be awaited. It should also be noted that,
due to the relatively small numbers of available subjects, there is a
wide variation of the confidence intervals around some LR
estimates, and the true final odds may be refined once additional
data from other ongoing projects are available.
In conclusion, the present data provide evidence that the
diagnosis of VWD, particularly in patients with modestly reduced
VWF levels and few bleeding symptoms, could be very uncertain.
Sound diagnostic criteria should be based on laboratory data,
personal bleeding history, and family data, and a quantitative
approach could be useful to exploit all the gathered information.
Analysis of other cohorts of patients is, however, required to test
the predictive value and clinical usefulness of this approach for
diagnostic and prognostic purposes.
4003
Acknowledgments
We thank J. C. J. Eikenboom and A. B. Federici for critically
reviewing the paper. Gratitude is due to the following colleagues
who participated in the IMS-VWD and MCMDM-1VWD studies:
Czech Republic: D. Habart, Z. Vorlova; Denmark: J. Ingerslev;
France: J. Goudemand, C. Mazurier, D. Meyer; Germany: U.
Budde, R. Schneppenheim; Italy: F. Baudo, A. Cappelletti, S.
Linari; India: A. Srivastava; Spain: J. Batlle, P. Casaña; Sweden: L.
Holmberg, S. Lethagen; United Kingdom: A. Goodeve, F. Hill, J.
Pasi, I. Peake; Venezuela: N. De Bosch.
This work was supported in part by grants from Associazione
Veneta per l’Emofilia e le Coagulopatie (AVEC) and from Fondazione Progetto Ematologia, both in Vicenza, Italy.
Authorship
Contribution: A.T. designed the research, performed statistical
analysis, and drafted the paper; G.C. and F.R. designed the
research, interpreted data, and revised the paper.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Francesco Rodeghiero, Department of Hematology, San Bortolo Hospital, 36100 Vicenza, Italy; e-mail:
[email protected].
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From www.bloodjournal.org by guest on July 31, 2017. For personal use only.
2008 111: 3998-4003
doi:10.1182/blood-2007-08-105940 originally published
online January 10, 2008
Evidence-based diagnosis of type 1 von Willebrand disease: a Bayes
theorem approach
Alberto Tosetto, Giancarlo Castaman and Francesco Rodeghiero
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