Download Hemorrhage Data

Benjamin Norment and Dylan O’Shea
MATH 157
November 10, 2008
Hemorrhage Data Set
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O'Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, et al.
(2000). "Apolipoprotein E genotype and the risk of recurrent lobar intracerebral
hemorrhage." N Engl J Med; 342:240-5.
The goal of this study was to test if the apolipoprotein E genotype was a factor in
recurrent lobar hemorrhage. Previous studies have shown that the 4 and 2 alleles
of the apolipoprotein E genotype could be potential indicators of cerebral amyloid
angiopathy, a significant contributor to intracerebral hemorrhage in the elderly.
While patients generally survive the initial lobar hemorrhage, recurrent lobar
hemorrhages are common and may carry a greater risk of morbidity and mortality.
The study found that carriers of the 2 or 4 allele of the apolipoprotein E genotype
had a two-year rate of recurrence of 28 percent, while non-carriers had only a 10
percent rate of recurrence over 2 years, indicating that the apolipoprotein E
genotype is a useful indicator of early recurrence of lobar hemorrhage in the
elderly.
No treatment was given as this was an observational study
The experiment was an observational study conducted on patients over the age of
55 who were admitted to the Massachusetts General Hospital or the Spaulding
Rehabilitation Center in Boston with primary lobar hemorrhage. Any patients
who displayed hemorrhage outside of the lobar regions, had another definite cause
of hemorrhage, or died before being discharged from the hospital, were excluded
from the study. 197 elderly patients with intracerebral hemorrhage were screened
for the study, of these 103 did not have another definite cause for hemorrhage. 78
of these patients survived until being discharged from the hospital. Of these, 71
agreed to participate in the study, and these patients, or their caregivers, were
interviewed by telephone every six months after hospital release. They were asked
if the patient had any experienced any type of stroke or decline in memory,
language or other cognitive functions. Reports of recurrent lobar hemorrhage
were confirmed by review of medical records, CT scans, and pathological
specimens. DNA testing through blood samples determined the presence of the 2
or 4 allele of the apolipoprotein E genotype. 14 patients were censored in the
study due to death from causes other than recurrent hemorrhage and 4 patients
were censored because the researchers lost contact with them. Patients who died
during the study as a result of recurrent hemorrhage were not censored. The study
was funded through grants from the National Institutes of Health, the American
heart Association, and the Edward Mallinckrodt Jr. Foundation.
As previously stated, subjects were removed from the study if they had another
definite cause for hemorrhage, displayed hemorrhage outside of the lobar region,
or did not survive to be discharged from Massachusetts General Hospital.
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Variables:
“genotype” = If the patient was a carrier of the 2 or 4 allele of the
apolipoprotein E genotype
0 = Non-Carrier (e3/e3 genotype)
1 = Carrier (e2 or e4 genotype)
“time” = Follow up time in months
“recur” = Did the patient have a recurrent lobar hemorrhage
0 = No recurrence
1 = Recurrence
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One patient died prior to giving blood for apolipoprotein E testing and thus no
genotype data is available for this patient.
Surprisingly, age, sex, dementia, and diabetes mellitus were not correlated with
significant changes in time of recurrence. A history of hemorrhagic stroke was
correlated with an elevated risk of early recurrent lobar hemorrhage, however this
was concluded to be due to its role as a marker of other risk factors, rather than a
causal role. Of special note, hypertension did not appear to affect the risk of
recurrence, although it has previously been shown to be a risk factor for
hemorrhage in elderly patients.
Summary Statistics
Distribution of recurrence among Carriers and Non-Carriers:
e2/e4 “carrier” genotype
14
24
Recurrence
No Recurrence
Non-Carrier
4
28
Distribution of Follow-up times for Patients (Months after Initial Hemorrhage)
All Patients
Carrier
Non-Carrier
Recurrence
NonRecurrence
Min
0.23
1.380
0.23
0.23
1.051
1st Quart
10.07
5.684
18.03
3.187
14.410
Median
19.75
17.940
26.56
9.528
23.010
Mean
22.50
19.220
27.06
14.260
25.510
3rd Quart
36.63
29.021
38.05
24.820
38.640
Max
53.88
46.880
53.88
42.870
53.880
We see that there are noticeable differences between the mean and median follow-up
times for carrier patients vs. non-carriers, and for patients with recurrent hemorrhaging
vs. patients without recurrence. We will later test these differences with a t-test to
determine if they are statistically significant.
Descriptive Graphics
Below are visual representations of the distribution of follow-up times for carrier
patients, non-carrier patients, recurrent hemorrhage patients and non-recurrent patients.
Box plots for our aggregate followup times are provided as reference.
Box Plots of Follow-up Times for Patients in different groups
Inference Data
In order to test the null hypothesis that the mean follow-up time for our carriers was
equal to the mean follow-up time for non-carriers, we performed a two-sided, unpaired ttest of the follow-up times of the two groups.
Doing so gave us a t-value of 2.2208, corresponding with only a 2.983% probability
that we would observe such extreme data given that the null hypothesis is true. We
obtained a 95% confidence for the difference in means of the two groups. Thus we reject
the null hypothesis and are 95% confident that non-carriers received between 0.790865
and 14.892911 more months of follow-up than carrier patients. We conclude that followup time of non-carriers was significantly higher than that of carriers. However, this is
likely not due to any mistake or bias in experimental design. Proportionally more of the
carrier individuals displayed recurrent hemorrhaging during the follow-up time, at which
point follow-up for these individuals was halted. Thus, it is actually to be expected that
follow-up time for non-carriers would be higher.
We likewise performed a two-sided, unpaired t-test to determine whether the mean
follow-up time for individuals with recurrent hemorrhaging differed significantly from
individuals without recurring hemorrhaging. Our null hypothesis is that the mean followup times for the two groups are the same.
Performing this second t-test gave us a t-value of 2.9794, corresponding with only a
0.5318 % probability that we would observe such extreme data given that the null
hypothesis is true. We obtained a 95% confidence for the difference in means of the two
groups. Thus, we reject the null hypothesis and are 95% confident that non-recurring
patients received between 3.575 and 18.93 more months of follow-up than patients with
recurring hemorrhaging. We conclude that follow-up time of non-recurrent patients was
significantly higher than that of recurrent hemorrhage patients. However, this is not due
to any flaw or bias in experimental design or followup. Rather, follow-up for patients
was halted as soon as they displayed recurrent hemorrhaging, and thus follow-up time for
recurrent hemorrhage patients must necessarily be lower than for patients who did not
display recurrent hemorrhaging.
Furthermore, we performed a simple logistic regression of genotype on recurrence to
determine whether the carrier genotypes (e2, e4) are significant predictors of recurrent
hemorrhaging. We found that the odds of recurrence for carrier genotype individuals is
4.083278 times that of non-carrier individuals. The 95% confidence interval for this
odds ratio is (1.184309, 14.078), and the p-value associated with the odds ratio is 2.59%.
Thus we can reject that the null hypothesis that carrier genotype is not a significant
predictor of recurrent hemorrhaging. We conclude that carrier genotype is a significant
predictor of recurrent hemorrhaging (as concluded in the O’Donnell study), and can
conclude that we are 95% confident that carrier genotype is associated with an odds ratio
of recurrent hemorrhage between 1.184309 and 14.078 times that of non-carrier
individuals.