Validation of Early Predictors of
Outcome in the Dallas Newborn Cohort
INTRODUCTION
Sickle cell disease (SCD), an inherited disorder of hemoglobin that leads to abnormally
shaped and dysfunctional red blood cells, affects over 70,000 Americans. SCD affects up
to 60% of populations in various areas throughout Africa. Naomi Marshall, a forty-one
year old woman with SCD, tells us of her own experiences as a child:
When I was three years old I was diagnosed with sickle cell anemia.
The only thing my parents knew about the disease was what they had
heard: people who had it lived short, painful lives. My parents told
me that I probably wasn’t going to live very long. [So] I pretty much
shut down. I never thought I would grow up. For the most part I
just concentrated on alleviating the worst part of the disease: my
day-to-day pain. When I was younger the pain affected my ankles,
feet and hands. Now that I am older, it affects my legs, back and
hips. (Scott 2002)
Normally round, flat and flexible, red blood cells contain hemoglobin, which transports
oxygen in the blood. Their flexibility and natural shape enable the cells to pass through
tiny capillaries that connect arteries and veins, where oxygen is released and carbon
dioxide, a waste product, is picked up. Due to a mutation in the globin genes composing
hemoglobin, patients with SCD have red blood cells that twist out of shape because of the
formation of polymers, or crystals, of abnormal hemoglobin within them (Figure 1). As a
result, sickled red blood cells are unable to readily pass through small blood vessels,
leading to the damage of organs and excruciating pain. (Beshore,1994)
2
Figure 1: Sickled erythrocytes. (American Medical
Association (1974) Archives of Internal Medicine. 133:4
(cover).)
3
BACKGROUND
In Western medicine, the first case of SCD was noted by Dr. James Herrick (1910) when
he described a patient of eastern Caribbean descent admitted to Presbyterian Hospital,
Chicago, in late 1904. Examination of this patient’s blood revealed erthyrocytes, or red
blood cells, with ‘very irregular (and) elongated’ shapes. These observations were
subsequently followed by several more cases including those reported by Washburn in
1911 and Emmel in 1917. Findings by Emmel (1917) raised suspicions of a genetic
basis, since several siblings of the patients had died from severe anemia, and blood from
the patient and her asymptomatic father showed a sickling deformity of the red cells on
incubation (Emmel, 1917). This proposal was further refined by Taliaferro & Huck
(1923) when a pedigree of Huck’s patients led to the conclusion that sickle cell disease
was inherited as a Mendelian autosomal recessive trait.
Individuals with SCD have red blood cells (RBC) that contain hemoglobin S (HgbS) as
opposed to normal hemoglobin, hemoglobin A (HgbA). The quaternary structure of
hemoglobin is defined by two α globins and two β globins, each attached to a heme group
that reversibly binds to O2 (Figure 2). The main role of hemoglobin is the transport of O2
throughout the body. HgbS results from a point mutation of the β globin chain where the
amino acid valine replaces glutamic acid at the sixth position. Sickling of HgbScontaining RBCs is promoted by low oxygen tension and acid conditions (Hahn &
Gillespie, 1972). The point mutation produces a hydrophobic contact point, causing
polymerization of HgbS in the deoxygenated state, thus damaging RBC membranes and
inducing vaso-occlusion, or blood vessel obstruction (Steinberg, 1999).
4
Figure 2: Hemoglobin molecule with 2 α globins and two β globins, each
attached to a heme group that reversibly binds to O2. (American Medical
Association (1974) Archives of Internal Medicine. 133:4, 541.)
Four major types of SCD have been identified since the first observations by Dr. Herrick
(1910). The most common and severe form of SCD is sickle cell anemia (SS), the
homozygous state for hemoglobin S. Less common forms of SCD include sicklehemoglobin C disease (SC), sickle-β+-thalassemia (Sβ+), and sickle-β0-thalassemia (Sβ0).
These latter forms of SCD are the result of compound heterozygous states with Hgb S
and other hemoglobinopathies, such as Hgb C and β-thalassemia. Although
genotypically distinct, sickle cell anemia and sickle-β0-thalassemia are considered
phenotypically similar in regards to disease symptoms and severity. Likewise, sicklehemoglobin C disease and sickle-β+-thalassemia, which are less severe forms of sickle
cell disease, are considered to be phenotypically analogous.
5
SYMPTOMS AND COMPLICATIONS
SCD is a multi-system disorder characterized by a chronic hemolytic anemia, where
erythrocytes rupture, or lyse, prematurely. Much of the pathophysiology of SCD is
thought to result from vaso-occlusion by sickle erthryocytes, which leads to a wide
variety of events that may require medical attention, and includes: painful crisis, splenic
involution, stroke, and acute chest syndrome.
Painful Crisis. SCD is a disease that causes pain. As the hallmark of the disease, painful
crisis is currently the most frequent cause of recurrent morbidity in SS disease and
accounts for a large portion of sickle cell-related hospital admissions (Baum et al, 1987).
Hertz Nazaire, a Haitian artist who lives with SCD, skillfully depicts his suffering from
SCD pain (Figure 3)
Figure 3: Ten Redefined by Hertz Nazaire
6
According to Felix (1974) the pain is persistent and unyielding, continuous with a
throbbing character.
“American patients in sickle cell crisis describe the pain as ‘gnawing
me down,’ ‘cutting me to pieces,’ ‘like toothache,’ or they say they are
‘in a rate’ or ‘on a rack’… [In parts of Africa] the tribal names for the
disease often reflect the harrowing experience of the sufferer. Adep,
which is the Cameroon term for the disease, means ‘beaten up,’
reflecting the sore feeling that patients have all over when the crisis is
ended. Hemkom (Adangme tribe) means ‘body biting,’ while nuidudui
(Ewe tribe) means ‘body chewing.’ (Felix, 1974)
Factors that may lead to painful crisis include skin cooling, infection, and dehydration.
Treatment includes rest, warmth, and rehydration but most attention has been directed to
the pharmacological relief of pain (Serjeant, 2001).
Splenic Involution. Splenomegaly, the enlargement of the spleen, is common among
young SCD patients (Jamison, 1924; Archibald 1926 & Alden, 1927). Tomlinson (1945)
asserted that splenic pooling is the result of entrapment of circulating sickled cells.
Wollstein & Kreidel (1928) observed that the spleen was frequently enlarged in young
children with SCD and would become smaller with age. The spleen becomes enlarged by
the chronic entrapment of sickled cells. Early loss of splenic function (Pearson et al,
1969) renders patients prone to overwhelming septicemia, or blood poisoning, especially
with pneumococci, the most common cause of bacterial pneumonia, meningitis, and
sepsis in SCD. As a result, young children with SCD are prescribed prophylactic
penicillin to prevent pneumococcal infections (John et al, 1984 & Gaston et al, 1986).
7
Stroke. Stroke is a devastating complication that occurs in a minority of children with
SCD with a frequency of approximately 0.5% per year (Ohene-Frempong, 1998). Major
distinguishing clinical features of stroke in patients with SCD include the young age of
involvement with a median age of 6 years, and the high proportion of cerebral infarction
in children and hemorrhage in adults (Powars et al, 1978; Balkaran et al, 1992).
According to Quinn (2004), 11% of children will suffer a clinically overt stroke by 18
years of age. Nearly an additional 20% of patients will have a clinically “silent” stroke
(Moser, 1996). Although mortality due to initial stroke is low, morbidity is considerable,
with sometimes permanent motor and neuropsychological deficits (Armstrong, 1996).
Acute chest syndrome (ACS). ACS is a descriptive name for a variety of acute pulmonary
illnesses in individuals with SCD (Charache, 1979). A pneumonia-like illness, ACS
causes significant morbidity and mortality (Platt, 1994; Vichinsky, 2000 &
Vichinsky,1997). It is the second most common reason after painful crisis for
hospitalization and the most common cause of death for individuals with SCD. Although
ACS is similar to a vaso-occlusive crisis, it involves the lungs rather than other organs,
sometimes leading to life-threatening respiratory failure. Individuals with SCD who
experience repeated ACS episodes may also be predisposed to scarring and pulmonary
hypertension (Oswaldo et al, 1994).
8
AVAILABLE THERAPIES
Besides education, immunization, and regular monitoring, there is no specific
intervention for individuals with SCD. However, current therapeutic options include
hydroxyurea, regular red blood cell transfusions, and stem cell transplantation.
Hydroxyurea is currently prescribed to SCD patients to decrease the number of SCDrelated complications. It functions by increasing the amount of fetal hemoglobin in the
blood, which in turn decreases the level of HgbS. A randomized placebo-controlled
clinical trial, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH),
revealed a significant decrease in incidence of painful episodes in patients administered
hydroxyurea along with a significantly lower number of hospitalizations. Additionally,
ACS developed in only 25 patients in the hydroxyurea group, compared to 51 patients on
placebo (Charache et al, 1995, 1996).
Once a patient has a stroke, subsequent strokes are likely but can be prevented by
monthly blood transfusions which reduce the proportion of sickling cells in the blood
stream (Russell et al, 1984 & Pegelow et al, 1995). These transfusions usually continue
indefinitely. Transfusion programs may also be utilized to decrease the frequency of
vaso-occlusive events (Leitman et al, 1991 & Wayne et al, 1993).
Currently, the only cure for SCD is bone marrow transplantation. However, the high
morbidity and mortality linked to the procedure has generally limited its use to severely
affected individuals with SCD. Furthermore, other problems include the low availability
of suitable donors and complications including acute and chronic graft-versus-host
9
disease, a condition where cells from the transplanted donor tissue initiates an
immunologic attack on the cells and tissue of the recipient, and graft rejection in
approximately 10% of cases (Bernaudin et al, 1997 & Vermylen et al, 1997).
10
OBJECTIVE
SCD is quite phenotypically variable: some individuals with SS have frequent vasoocclusive complications and die young, whereas others seem little affected by the disease
and may have a normal lifespan (Serjeant, 1968 & Steinberg, 1973). The Cooperative
Study of Sickle Cell Disease (CSSCD) reported in 1994 that the median lifespan of men
and women with SS was 42 and 48 years, respectively, (Platt et al, 1994) and the death
rate in 2,824 enrolled children with 0.5 deaths per 100 patient years (Leikin et al, 1989).
Quinn et al. (2004) reported an overall survival of 86% and a death rate of 0.59 per 100
patient-years for children with SS followed from birth through 18 years of age. Thus, the
morbidity and mortality of SCD are significant, but not all individuals are affected
equally by the disease.
As such, the prediction in very early childhood of later severe disease would permit riskbased counseling for families, help justify the early use of disease-modifying or curative
treatments, like hydroxyurea, chronic transfusions, or bone marrow transplantation, and
provide the opportunity to better balance the risks of these interventions with risks of the
sickle cell disease itself.
In the past several years, studies have been conducted to construct early predictive
models for SCD. Miller et al. (2000) used multivariate analysis, which is the observation
and analysis of more than one statistical variable at a time, to test several potential risk
factors in the CSSCD infant cohort. Adverse outcomes were defined as death, stroke,
recurrent pain episodes (greater than two per year on average over the course of follow-
11
up) and recurrent ACS (greater than one per year on average over the course of followup). Of the factors analyzed, Miller found that those infants with SS or Sβ0 who had a
hemoglobin concentration below 7 g/dL in steady-state during the second year of life,
those with elevated white blood cell (WBC) count, and those who experienced an episode
of dactylitis, or painful swelling of fingers or toes, before one year of age were at
significantly increased risk of an adverse clinical outcome (Figure 4).
Figure 4: Estimated Probability of Severe Sickle Cell Disease by the Age of 10 Years According to the
Leukocyte Count, Severe Anemia during the Second Year of Life, and the Occurrence of Dactylitis before
the Age of 1 Year. Severe anemia was defined as a hemoglobin level of less than 7 g per deciliter during
the second year of life. In this cohort of patients, 3 percent were classified as being at high risk, 53 percent
were classified as being at medium risk, and 44 percent were classified as being at low risk (From Miller
ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, et al. Prediction of adverse outcomes in
children with sickle cell disease. N England J Med. 2000; 342 (2): 86.
Miller’s model is notable because it uses easily identifiable predictors in early life.
However, it is not known if this model is still valid, since the second most commonly
predicted adverse outcome -- death from SS -- has become increasingly infrequent due to
improvements in the health care of individuals with SCD. For example, most of the
deaths (56%) in this study were from infection, which is now a rare event because of
12
universal newborn screening, prophylactic penicillin, and conjugated pneumococcal
vaccines which are administered to young children with SCD.
The primary aim of this project is to validate the model of Miller et al. in the Dallas
Newborn Cohort, the world’s largest newborn inception cohort of sickle cell disease
(Quinn et al. Blood 2004; 103:2043.). Specifically, we test the predictive utility of three
clinical findings in the first years of life: painful swelling of the hands and feet
(dactylitis), severe anemia (Hgb <7 g/dL), and elevation of the white blood cell count
(leukocytosis) for later complications of sickle cell disease, which includes death, stroke,
painful episodes, and ACS.
13
MATERIALS AND METHODS
The Dallas Pediatric Sickle Cell Program is located in Children’s Medical Center Dallas
on the campus of the University of Texas Southwestern Medical Center at Dallas (UT
Southwestern). It is the referral center for children with SCD in most of northeast Texas.
Its area of inclusion consists of a pediatric population of approximately 1.3 million,
including both urban and rural communities. Since 1977, all children with SS and Sβ0
have been uniformly prescribed oral prophylactic penicillin until at least five years of
age. All children with SCD are immunized with 2 doses of the 23-valent pneumococcal
polysaccharide vaccine at two and five years of age. Universal newborn screening for
hemoglobinopathies in Texas began November 1, 1983. Children with SCD are
evaluated as soon as possible after diagnosis; children with SS and Sβ0 are evaluated in
the clinic every three to four months when younger than 3 years of age, every 4 to 6
months from 3 to 5 years of age, and every 6 to 12 months thereafter.
The study subjects were selected from the Dallas Newborn Cohort that includes a total of
711 patients with different forms of sickle cell disease. This cohort is defined to include
all children who were (1) born in Texas on or after November 1, 1983; (2) identified to
have a form of SCD by the NBS program of the Texas Department of Health (Therell et
al 1983); (3) evaluated at least once in the sickle cell clinic at Children’s Medical Center
Dallas; (4) and confirmed to have either SS, SC, Sβ0, or Sβ+. This study analyzed a
subset of this cohort of approximately 120 patients. Study subjects were selected based
on the following criteria: (1) diagnosis of sickle cell anemia (SS) or sickle-β0-thalassemia
(Sβ0), (2) age ≥5 years, (3) not receiving chronic red blood cell transfusions in the first 2
14
years of life, and (4) complete medical records. Subjects were included regardless of
gender or race, however most individuals who have sickle cell disease in the United
States are African-American.
Patient-related information was obtained from subjects’ medical records at Children’s
Medical Center Dallas, which is affiliated with the University of Texas Southwestern
Medical Center at Dallas (UT Southwestern) and regulated by the UT Southwestern
institutional review board (IRB). Three separate sources comprise these medical records:
(1) the electronic sickle cell database, (2) the electronic medical record, and (3) the
archived paper-based medical record. These three sources were systematically reviewed
to determine subjects’ blood count values in the first 2 years of life, the occurrence of
dactylitis in the first year of life, and later adverse outcomes (death, stroke, pain, and
ACS).
To apply the Miller model to the Dallas Newborn Cohort, the following early predictors
were used:
(1) Early dactylitis: dactylitis occurring in the first year of life
(2) Severe anemia: average hemoglobin concentration <7 g/dL recorded during
steady-state (“well visits”) in the second year of life
(3) Leukocytosis: average white blood cell (leukocyte) count > 20,000 /mm3
recorded during steady-state visits in the second year of life.
This designation for leukocytosis was applied because the highest risk children in the
CSSCD infant cohort (Figure 4), analyzed by Miller et al., were those with (1) severe
15
anemia and early dactylitis, (2) severe anemia and white blood cell count > 20,000 /mm3,
or (3) dactylitis and leuckocyte count approximately >20,000 /mm3.
Identical to Miller’s model, the following were determined as adverse outcomes:
(1) Death
(2) Clinically overt stroke
(3) Frequent pain (two or more painful events per year for the entire follow-up
period, with at least two events per year for three consecutive years)
(4) Recurrent ACS (one or more episode of ACS per year for the entire follow-up
period, with at least one episode per year for three consecutive years).
Any patient who has one of these outcomes is defined as having “severe disease”.
In the Miller model, patients flagged as more likely to have adverse outcomes were those
who had two or more of the predictors identified above. Similarly, in my study, the same
criteria were used to make predictions of adverse outcomes, so as to be consistent with
the Miller model. Thus, a patient with early dactylitis and leukocytosis would be
predicted to have an adverse outcome in our study.
The effectiveness of the model as it applies to the Dallas Newborn Cohort was
investigated using two separate methods. To determine whether the Miller model could
properly identify children who experience adverse outcomes in the Dallas cohort, several
standard clinical test measures were initially carried out: sensitivity, specificity, positive
predictive value (PPV) and negative predictive value (NPV). Then, binary logistic
16
regression was used to determine the performance of the model, taking into consideration
raw data rather than using Miller’s published risk groups and associated cut-off values for
hemoglobin (<7 g/dL) and leukocyte count (> 20,000 /mm3). Similar to linear regression,
logistic regression models the predictors for a categorical outcome (i.e., adverse event:
yes or no) instead of a continuous or numerical outcome (i.e., 1, 2, 3, etc.).
17
DATA ANALYSIS
A total of 119 subjects were eligible for analysis (Table 1). Early predictive events
occurred at the frequencies shown in Table 2. A total of 18 (15.1%) patients suffered an
adverse event, as illustrated in Table 3.
Table 1: Characteristics of Subjects
Descriptor
Value
Number
Sex (% male)
Genotype (% SS)
Age (years)
Mean
Median
Range
119
68
97
9.7
9.2
5 – 15.4
Table 2: Early predictors
Early predictors
Subjects
Dactylitis before 1 yr of age
Hgb ≤ 7 g/dL in 2nd yr of life
WBC ≥20,000 /mm3 in 2nd year of life
24 (20.2%)
5 (4%)
15 (12.6%)
Mean Range
N/A
8.8(6.1 – 13) g/dL
14,560(5830 – 34,300) /mm3
Table 3: Adverse Events
Adverse Event
Subject
Death
Stroke
≥2 Painful events/yr
≥1 Episode of acute chest syndrome/yr
Total
2 (1.7%)
13 (10.9%)
3 (2.5%)
1 (0.8%)
18 (15.1)*
* one patient had two adverse outcomes
As shown in Table 4, the utilization of the Miller model in the Dallas Newborn Cohort
revealed a sensitivity of 0% and a specificity of 97%. Sensitivity refers to the proportion
of patients with severe disease who are correctly identified by the set of early predictors
[true positives/ (true positives + false positives)]. Specificity indicates the proportion of
18
patients without severe disease who are correctly identified [true negatives/(true
negatives + false negatives)]. The positive predictive value (PPV) was 0% and the
negative predictive value (NPV) was 84%. The PPV refers to the likelihood of having
severe disease given a positive test. Similarly, the NPV is the likelihood of not having
severe disease given a negative test.
Table 4: Miller et al Model in the Dallas Newborn Cohort
Predicted to be
Severe
Predicted to Not
be Severe
Totals
Patients with
Severe Disease
0
Patients without
Severe Disease
3
Totals
3
18
98
116
18
101
119
Using binary logistic regression, the dependent variable was set as any adverse event (yes
or no) and the independent (predictor) variables were: dactylitis in first year of life (yes
or no), hemoglobin level in the second year of life (as a continuous variable, g/dL), and
leukocyte count in the second year of life (as a continuous variable, /mm3). Tested as a whole,
the model was not determined to be significant, with a P value of 0.2145, indicating that
the Miller model is not an accurate model for disease outcome in the Dallas Newborn
Cohort. Furthermore, the coefficient of determination (R2), which is a measure of the
correlation between dependent and independent variables in regression analysis, was
0.0443, indicating that most of the variability in adverse outcomes is not related to the
designated predictors.
The receiver operating characteristic (ROC) curve (Figure 5) allows for the determination
of better directed cut-points by plotting sensitivity versus 1-specificity across all possible
19
combinations of hemoglobin, leukocyte count, and dactylitis. It demonstrates the
relationship between sensitivity and specificity of the model without identifying specific
cut-points (e.g. Hgb <7). This allows for a complete illustration of tradeoffs between true
positives and false positives at each combination. The area under the curve (AUC) is
small (0.63586) and the line is nearly straight, further indicating that this is a very poor
predictive model.
Figure 5: Receiver operating characteristic for the prediction of
adverse events by the early predictors
20
DISCUSSION AND CONCLUSION
The predictive utility of the Miller model is fairly poor in the Dallas Newborn Cohort.
None of the patients with an adverse outcome was properly identified by the model. A
prediction of severe disease indicated a 0% chance of actually having severe disease.
Sensitivity was high (97%) but this was propelled by the fact that many subjects never
experienced an adverse outcome. The NPV was lower, at 84%, indicating a large
possibility of misclassification even with a negative test.
The poor performance of the model was also revealed using logistic regression in place of
Miller’s designated cut-offs. There was no statistically significant prediction of an
adverse outcome by any combination of early dactylitis in the first year of life, Hgb
concentration in the second year of life, and leukocyte count in the second year of life.
Furthermore, the area under the ROC curve was low at 0.64. A perfect test has an AUC
of 1, and a test that is level with chance has an AUC of 0.5.
In conclusion, the Miller model is not practical, at any level, to operate as a guide to
influence clinical decisions about early disease-modifying interventions for young
children with SCD. These findings are unfortunate since no other predictive model using
easily identifiable predictors in early life exists. Yet, the use of an inaccurate model will
expose children with SCD to the risks of early interventions that may not be necessary.
As such, further investigation and research is clearly needed in this field.
21
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