American Journal of Epidemiology Vol. 143, No.

5
Copyright © 1998 by The Johns Hopkins University School of Hygiene and Public Hearth Printed In U.S.A
AU rights reserved

Effectiveness of Contact Isolation during a Hospital Outbreak of Methicillin-

resistant Staphylococcus aureus

John A. Jernigan,1 Maureen G. Titus,1 Dieter H. M. Grbschel,1 Sandra I. Getchell-White,1 and Barry M. Farr1

Contact isolation has been recommended by the Centers for Disease Control and Prevention for the
prevention of nosocomial transmission of methicillin-resistant Staphylococcus aureus (MRSA), but there are
few data which prospectively quantitate the effectiveness of contact isolation for this purpose. During an
outbreak of MRSA in a neonatal intensive care unit between July 18, 1991 and January 30, 1992, weekly
surveillance cultures were performed on all patients. Sixteen of 331 admissions became colonized with MRSA,
and 3 (19%) developed infections: bacteremia, conjunctivitis, and dialysis catheter site infection. The isolates
from all 16 patients were submitted to plasmid profile analysis and restriction enzyme analysis of whole cell
DNA. All of the patients had identical chromosomal patterns and plasmid profiles, which differed from control
isolates from other wards, indicating that the outbreak resulted from spread of a unique strain. None of 144
personnel who were cultured after recent contact with newly colonized patients during the outbreak were
found to carry MRSA, which suggests that patients were the reservoir for transmission rather than caregivers.
The most probable source for each individual transmission was determined based on proximity in time and
space and shared exposure to caregivers. The rate of transmission of MRSA from patients on contact isolation
was significantly lower (0.009 transmissions per day on isolation) than the rate for patients not on isolation
(0.140 transmissions per day unisolated, relative risk = 15.6, 95% confidence interval 5.3-45.6, p < 0.0001).
The authors conclude that the risk of nosocomial transmission of MRSA was reduced 16-fold by contact
isolation during the outbreak in this neonatal intensive care unit. These data confirm the results of previous
studies which have suggested that contact isolation was effective in controlling the epidemic spread of
methicillin-resistant Staphylococcus aureus. Am J Epidemiol 1996;143:496-504.

cross infection; infection control; intensive care units, neonatal; methicillin resistance; Staphylococcus
aureus

Staphylococcus aureus resistant to methicillin
(MRSA) has become an increasingly important noso-
comial pathogen in US hospitals. Data from the Na-
tional Nosocomial Infection Surveillance System
(NNIS) show that the proportion of 5. aureus isolates
resistant to methicillin has increased from 2 percent to
29 percent in NNIS hospitals during the last 15 years
(1). MRSA has spread rapidly in many hospitals, caus-
ing substantial morbidity and mortality (2). Although
methicillin-resistant and methicillin-sensitive strains
of S. aureus (MSSA) have had similar virulence in
animal models (3), one prospective study demon-
strated a significantly greater risk of staphylococcal
Received for publication August 11,1994, and in final form June
29, 1995.
Abbreviations: DNA, deoxyribonucletc add; MRSA, methicillin-
resistant Staphylococcus aurmis; MSSA, methicillin-sensitive
Staphylococcus aumus; NICU, neonatal intensive care unit; NNIS,
National Nosocomial Infection Surveillance System.
1
University of Virginia Health Sciences Center, Chariottesville,
VA.
Reprint requests to Dr. Barry M. Farr, University of Virginia Health
Sciences Center, Box 473, Chariottesvtlle, VA 22908.
infection in patients colonized with MRSA compared
with those colonized with MSSA (4). Some investiga-
tors have reported that increasing rates of MRSA
infection have increased the total endemic rate of 5.
aureus infections rather than merely replacing an
equal number of methicillin-sensitive 5. aureus infec-
tions (5-7), although other investigators have not con-
firmed this finding (8, 9). There is concern that van-
comycin use may increase substantially as MRSA
becomes more prevalent, resulting in increased selec-
tion pressure for vancomycin-resistant organisms (10).
For these reasons, many believe that efforts to control
MRSA are warranted (2, 10, 11). A recent survey of
US hospital epidemiologists (2) found that 91 percent
of the epidemiologists used MRSA control measures
of some kind in their hospitals.
Although barrier precautions are often included in
recommended control measures for MRSA (2, 10-
12), and are used by 76 percent of US hospitals (2), the
data on their effectiveness are conflicting. While some
studies have found a decrease in the incidence of

496
 Contact Isolation Effectiveness for Methicillin-resistant Staphylococcus aureus
endemic MRSA infection/colonization after adopting
barrier isolation procedures (8, 9, 13, 14), others have
failed to demonstrate a change in incidence using the
same or similar measures (15-17). To our knowledge,
no study has directly compared the rate of transmis-
sion of MRSA from unisolated patients with the rate of
transmission from patients who have been placed in
contact isolation.
During a 7-month outbreak of MRSA in a neonatal
intensive care unit in Charlottesville, Virginia, pro-
spective culturing and epidemiologic analysis allowed
measurement of transmission rates from unisolated
patients for comparison with the transmission rates
from patients who were in contact isolation.
MATERIALS AND METHODS
Description of the hospital and neonatal intensive
care unit
The University of Virginia Hospital is a 700-bed
hospital with nine intensive care units. The hospital
provides primary and tertiary care, and admits over
28,000 patients annually. The neonatal intensive care
unit (NICU) has 33 beds and admits approximately
700 neonates each year. The unit consists of four pods
containing 6-10 beds each, and an isolation room
containing an anteroom and two beds. One nurse gen-
erally cares for two infants during a single shift. When
a nurse leaves the unit during the shift, the nurse for an
adjacent patient will observe and provide emergent
care if needed. The pods are separated by partitions
interrupted by walkways through which personnel
pass from one pod to the other.
Routine MRSA control measures
The hospital infection control team, which consisted
of a hospital epidemiologist and four full-time infec-
tion control practitioners, conducted prospective sur-
veillance twice weekly within the unit using the
Kardex method (18). Clinical microbiology laboratory
results were monitored daily for isolates of MRSA
from any site. All patients colonized or infected with
MRSA were placed in contact isolation (12). This
consisted of wearing a mask when within 5 ft (1.5 m)
of the patient, a gown for direct contact with the
patient, and gloves for manual contact with the patient
or any other potentially contaminated surfaces. Con-
tact isolation was maintained until the time of dis-
charge from the hospital or eradication of colonization
had been documented. Roommates and other nearby
patients considered at risk were cultured to detect
MRSA colonization. Whenever positive results were
found, the area of surveillance was widened to assure
that additional undetected cases were not present. Sur-
Am J Epidemiol Vol. 143, No. 5, 1996
497
veillance cultures for detecting colonization were ob-
tained from the nose, axilla, and groin and, also, from
the site of any percutaneous device or skin wound.
Outbreak control measures
When the outbreak began, four additional control
measures were instituted:
1. Weekly surveillance cultures were obtained of
the nares, groin, axilla, and wounds (if present)
on all patients in the unit not previously known to
be colonized or infected with MRSA.
2. Staff compliance with control measures, includ-
ing diligent hand washing with chlorhexidine
soap, was repeatedly encouraged through discus-
sions with unit personnel and memoranda.
3. For selected patients, attempts at eradication of
colonization were made. Eradication regimens
were selected by the patient's primary physician.
Eradication was defined by three consecutive
daily cultures (nares, groin, axilla, wound, and
any other site known to be previously colonized)
beginning at least 72 hours after discontinuation
of antibiotics. Culture surveillance of previously
colonized patients was continued until hospital
discharge with four consecutive weekly cultures,
followed by monthly cultures.
4. Surveillance cultures were obtained from person-
nel who had had contact with new cases during
the 2 weeks preceding identification of a case by
conversion of surveillance cultures from negative
to positive. Cultures were obtained from the na-
res and any visible skin lesions of personnel.
Molecular typing of isolates
Plasmid profile analysis was performed after rapid
alkaline lysis of staphylococci according to Birnboim
and Doly (19) with the Kloos modification (20) of
substituting lysozyme with lysostaphin (100 ptg/ml)
and including a — 70°C freezing cycle in the extraction
step. Restriction enzyme fingerprinting of whole-cell
deoxyribonucleic acid (DNA) was performed accord-
ing to the method of Bialkowska-Hobrzanska et al.
(21).
Epidemiologic studies
The probable source for each transmission was iden-
tified through analysis of the following parameters: 1)
temporal relation between proposed source and recip-
ient; 2) geographic relation between proposed source
and recipient; and 3) personnel shared between the
proposed source and recipient. The analysis was per-
formed independently by two observers.
498 Jernigan et al.
Using prospective weekly culture results, the ap-
proximate day of acquisition of MRSA was deter-
mined for each patient. Because surveillance cultures
were obtained every 7 days, patients acquired MRSA
at some point between day 1 and day 7 following their
last negative culture. Acquisition was estimated to
have occurred at the midpoint of that interval, i.e., day
3.5. For patients exposed to a known source at some
time following their last negative culture, the date of
acquisition was estimated as the midpoint between
first exposure to the source and their first positive
culture. The end of the period of colonization within
the unit was defined as the date of discharge from the
unit or, if eradication attempts were successful, the
midpoint between initiation of eradication therapy and
the initiation of cultures that documented eradication.
Microbiology
Staphylococcus aureus was identified by standard
laboratory procedures (22). The determination of me-
thicillin-resistance was performed according to the
methods recommended by the National Committee on
Clinical Laboratory Standards for disk diffusion test-
ing (23), and the use of an oxacillin salt agar screening
plate (24).
Statistical methods
Rates were compared using the large-sample test for
comparison of incidence rates (25). Confidence inter-
7 * = Index Case
c A = Acquired MRSA from unisolated infant
to
5 --
4 --
o
o
o
II 2
2
1 4-
o M A 4 44
July Aug Sep Oct Nov Dec Jan
1991
FIGURE 1. Bar graph showing the prevalence of methidllin-resistant Stephytococcus aureus (MRSA) colonization during an outbreak in a
neonatal intensive care unit, Charlottesville, Virginia, 1991-1992. The arrows indicate the incidence of new cases (see key).
vals for simple proportions were determined using
published tables of exact confidence limits for bino-
mial distributions (26).
RESULTS
Description of the outbreak
In the 5 years preceding this outbreak, only four
sporadic nosocomial cases of MRSA colonization or
infection had been identified in the neonatal intensive
care unit. The outbreak occurred during the 7-month
period between July 18, 1991 and January 30, 1992
(figure 1). The index case was identified through an
eye culture of an infant with purulent conjunctivitis on
July 18, 1991. This patient had recently traveled out of
the NICU for a surgical procedure in the operating
room and was being followed by a non-NICU surgical
consultation team. Over the next week, four additional
cases were identified that were epidemiologically
linked to the index case (figure 2). Outbreak control
measures, including weekly surveillance cultures of all
patients in the unit who were not known to be previ-
ously colonized, were begun on July 30, 1991. Over
the next 6 months, 11 new colonizations or infections
were detected. By October 28, 71 days into the epi-
demic, there was only one remaining case in the NICU
isolation room. This case remained the only reservoir
in the unit for the ensuing 5 weeks before the next
transmission was detected. Surveillance cultures at the
end of that 5-week period revealed MRSA coloniza-
A = Acquired MRSA from isolated infant
4 5 1 A
Feb Mar Apr May Jun
1992
Am J Epidemiol Vol. 143, No. 5, 1996
 Contact Isolation Effectiveness for Methicillin-resistant Staphylococcus aureus 499

Transferred on 7/20
(7/24) T (7/24)

W22)

7/18-8/19

Isolation

uu uuuu
9/16-10/1

UU UUUU
10/28-12/2

Itotatkm ,~-\.~'

UU UUUU
12/13-1/7

(1/7)

UU _ U U UU UUUU
1/18- 1/30

Isolation
nn -" Bed not containing MRSA patient
Transmission from an unisotated infant at beginning of time period
Transmission from an isolated Infant Bed containing MRSA patient
Intraunft patient transfer at beginning of time period

FIGURE 2. Methicillin-resistant Staphylococcus aureus (MRSA) transmissions depicted in space and time in an outbreak in a neonatal
intensive care unit, Chariottesville, Virginia, 1991-1992. Five floor plans of the neonatal intensive care unit are shown. Each floor plan
corresponds to a time period during which transmissions occurred. Arrows indicate the donor and recipient of each transmission. Dates
indicate when cultures were recognized to be growing MRSA.

Am J Epidemiol Vol. 143, No. 5, 1996

500 Jernigan et al.
tion of three new babies located a considerable dis-
tance from the isolation room. The only personnel who
had shared care for the isolated baby and the others
were the attending and resident physicians. One of the
first-year residents, who reportedly had more manual
contact with the babies than the other physicians, had
been primarily responsible for case 8 in the isolation
room and also for new cases 12 and 13 (figure 2). At
least one colonized or infected infant remained in the
unit until April 27, 1992 (figure 1). Weekly surveil-
lance cultures of every infant in the unit was continued
for another 2 weeks, and no new cases were identified
during that period.
Five months after the final transmission of the out-
break and 6 weeks after discharge of the final patient
reservoir from the NICU, two new cases of MRSA
colonization with the outbreak strain were identified in
adjacent beds within the unit. One of these patients
had been admitted to the unit following discharge of
the last patient reservoir, and the patient developed
MRSA infection of a surgical wound. The other pa-
tient had been present in the unit during the period
when there were other patient reservoirs present, but
was culture-negative for MRSA for the duration of
weekly surveillance of the unit. Because no patient
reservoir existed in the unit at the time of acquisition,
extensive surveillance culturing of personnel was re-
peated. Two nurses were found to be colonized with
MRSA. One of these nurses (Nurse A) was epidemi-
ologically linked to the new cases. Nurse A had
worked with the last colonized infant in the isolation
room of the unit. She was found to be colonized with
the outbreak strain in the groin and at the site of an
eczematous lesion on her hand. This nurse had been
cultured during the outbreak and was negative at that
time. The other nurse (Nurse B), who had not worked
with any of the previous MRSA cases, worked with
the two new cases after Nurse A and prior to their
being isolated; she was colonized in the nares only.
The nurses' colonization was eradicated, as shown in
table 1. The infants were placed on contact isolation
and discharged within 3 weeks, and weekly surveil-
lance cultures of all patients were continued for an
additional 3 weeks following their discharge with no
positive results. No further cases of MRSA coloniza-
tion or infection were observed in the ensuing 44
months.
Description of the patients
During the 7 months, 16 (4.8 percent) of 331 neo-
nates admitted to the unit acquired MRSA. The most
common diagnoses among patients with MRSA infec-
tion or colonization were prematurity (87 percent),
patent ductus arteriosus (44 percent), pneumonitis/
respiratory distress syndrome (25 percent), and intra-
ventricular hemorrhage (19 percent). Thirteen of the
cases were colonized and three were infected. In ad-
dition to the index case (conjunctivitis), the infections
included a Tenkhoff dialysis catheter site infection and
one bacteremia. All three infections were successfully
treated with vancomycin. The most common sites of
colonization were nares (88 percent), umbilicus (56
percent), groin (50 percent), and axilla (31 percent).
Results of personnel cultures
None of the 144 personnel cultures taken during the
outbreak were positive for MRSA. During the inves-
tigation of the two cases which appeared after the
resolution of the outbreak, two (1.1 percent) of 181
personnel were found to be colonized.
Outcome of eradication regimens
Ten patients received therapy to eradicate coloniza-
tion and had evaluable outcome data. Eradication was
successful in seven of the 10 patients. The regimens
used and duration of follow-up are detailed in table 1.
Molecular typing
All 16 isolates had identical restriction fragment
profiles for total cellular DNA which clearly differed
from control MRSA isolates obtained from other
wards (figure 3). All 16 isolates contained a single
plasmid of identical molecular weight, which differed
significantly from the control isolates. The isolates
from the two patients and two personnel which were
discovered following resolution of the outbreak had
DNA restriction fragment length and plasmid profiles
identical to the original outbreak isolates and different
from controls.
Epidemiologic studies
There were 629.5 patient-days of MRSA coloniza-
tion during the outbreak. A total of 558 patient-days of
colonization were spent in contact isolation, and 71.5
patient-days of colonization were not spent in contact
isolation (table 2). In all, there were 15 transmissions,
giving a total rate of 0.17 transmissions per colonized
patient-week during the outbreak.
The results of epidemiologic tracing of the source of
the transmission by two independent observers were
100 percent concordant. Unisolated infants were
judged to be the source of 10 transmissions, while
isolated infants were believed to be responsible for
five transmissions (table 2).
Am J Epidemiol Vol. 143, No. 5, 1996
 Contact Isolation Effectiveness for Methicillin-resistant Staphylococcus aureus 501

TABLE 1. Summary of eradication data In an outbreak of methlcillln-reslatant Staphylococcus aureus

in a neonatal Intensive care unit, Charlottesvllle, Virginia, July 18,1991-January 30,1992

Patient Follow-up
Sites colonized Regimen (duration) Outcome
no. (days)
1 Nares Nasal muplrocin (14 days), Eradicated 14
vancomycin (7 days),
rifampln (4 days)

2 Nares, axilla, groin, Nasal mupirodn (2 days) Failed

umbilicus

8 Nares, umbilicus, Nasal + umbilical mupirodn Eradicated 45

urine (3 days)

10 Nares, axilla, groin, Nasal + umbilical mupirocin (7 Failed

umbilicus days), vancomycin (14 days),
removal of dialysis catheter

11 Nares, axilla, groin, Nasal + umbilical mupirocin (14 Eradicated 31

umbilicus days), vancomycin (14 days)

12 Nares, groin, sputum, Nasal + tracheostomy mupirocin Eradicated 80

tracheostomy (14 days), rtfampin (14 days),
TMP/SMX* (14 days),
chlorhexldlne baths (14 days),
change tracheostomy tube
(day 7)

13 Nares, axilla, groin, Nasal mupirocin (14 days), Eradicated 11

umbilicus chlorhexldine baths (14 days)

14 Nares Nasal mupirocin (14 days) Relapse at 18 days

-. 14 Nares Nasal mupirocin (11 days) Eradicated 11

15 Nares, umbilicus Nasal + umbilical mupirocin Eradicated 14

(13 days)

16 Nares Nasal + gastrostomy tube Failed

mupirocin (12 days)

16 Nares, axilla, groin, Nasal + gastrostomy tube Failed

umbilicus, mupirocin (14 days), change
gastrostomy tube gastrostomy tube

Nurse A Hand, groin Rifampin(IOdays), TMP/SMX Eradicated 67

(10 days)

Nurse B Nares Nasal mupirocin (10 days) Eradicated 76

' TMP/SMX, trimethoprim/sulfamethoxazole.

The relative risk of transmission from unisolated
patients was 15.6 compared with patients on contact
isolation (table 3).
DISCUSSION
The majority of the published literature supports the
concept that colonized patients are the major reservoir
for MRSA and that most transmissions occur via the
hands of hospital personnel. Although several studies
have examined the effect of isolation procedures in
controlling nosocomial transmission of MRSA, the
results have not been consistent (13-17, 27). Some
studies found a decrease in the incidence of endemic
MRSA infection/colonization after adopting barrier
isolation procedures, including one study conducted at
the University of Virginia Hospital more than a decade
ago (8, 9, 13, 14). Others have failed to demonstrate a
change in incidence with the use of the same or similar

Am J Epidemiol Vol. 143, No. 5, 1996

502 Jernigan et al.

Control TABLE 2. Summary of data regarding Isolation status of

donors and cases: outbreak of methicillln-reslstant
Staphylococcus auraus In a neonatal Intensive care unit,
July 18,1991-January30,1992
Isolation status Days spent
Days spent outside of
Case of donor
In contact
no. at time of contact
isolation
transmission Isolation

1 Unknown source 24 2
2 Unlsolated 63 3
3 Unisolated 8 3
4 Unisolated 13 2
5 Unisolated 9 2
6 Unisolated 46 5
7 Unisolated 41 9
8 Unisolated 116 5.5
9 Unisolated 11 5
10 Contact Isolation 21 5.5
11 Unisolated 16 5.5
12 Contact Isolation 42 4
13 Contact Isolation 8 5.5
14 Unisolated 44 3.5
15 Contact Isolation 7 5.5
16 Contact isolation 89 5.5

Total 558 71.5

TABLE 3. Rates of transmission In an outbreak of

methicillin-reslstant Staphylococcus aureus In a neonatal
intensive care unit, Charlottesville, Virginia, July 18,
1991-January 30,1992

Source of transmission
FIGURE 3. Electrophoresis patterns of a representative sample of
methicillin-reslstant Staphylococcus aureus (MRSA) isolates from Isolated Unisolated
an outbreak in a neonatal intensive care unit, Charlottesville, Vir-
Transmissions 5 10
ginia, 1991-1992, when subjected to restriction endonuclease di-
gestion. Lanes 1-5 are outbreak Isolates. The control lane is an Patient-days 558 71.5
MRSA isolate obtained from a different hospital ward. Rate of transmission 0.0090 0.140*
• Relative risk = 15.6, 95% confidence interval 5.3-45.6,
p < 0.0001.

measures (15-17). Murray-Leisure et al. (15) found

that contact isolation alone failed to control an epi-
demic in their hospital. It was only after intensifying
their surveillance efforts and aggressive cohorting of
personnel that they observed a decline in the incidence
of MRSA colonization. Reboli et al. (17) reported that
contact isolation failed to control an MRSA epidemic
in a neonatal intensive care unit until the initiation of
hexachlorophene handwashing. Rao et al. (16) also
observed that contact isolation failed to limit the
spread of an MRSA outbreak, but strict isolation was
successful in doing so. The only controlled study of
types of isolation for MRSA compared strict isolation
with modified contact isolation and failed to detect a
significant difference in rate of transmission, but the
study included only 20 cases and had only 23 percent
power to detect a 50 percent relative reduction in rate.
In this 7-month outbreak in a neonatal intensive care
unit, a combination of infection control measures,
including contact isolation, effectively controlled epi-
demic spread of a single strain of MRSA. Transmis-
sion of MRSA was 16 times more frequent from
unisolated patients during the outbreak than from pa-
tients in contact isolation.
The determination of comparative rates of transmis-
sion in this study depended on identification of the
source for each transmission. Although errors in iden-
tification of the source could have altered the results,
such errors were unlikely since two independent ob-
servers reached identical conclusions. Furthermore, in
the unlikely event that errors were made, the final
conclusions would not have been significantly af-
fected. For example, even if five of the 10 transmis-
sions attributed to unisolated infants had been misclas-
sified (i.e., the transmissions actually originated from
isolated patients), the rate of transmission from uniso-
lated infants would have remained significantly higher
than from isolated infants (relative risk = 4.7, 95
percent confidence interval 1.6-13.8).

Am J Epidemiol Vol. 143, No. 5, 1996

 Contact Isolation Effectiveness for Methicillin-resistant Staphylococcus aureus
It should be noted that MRSA colonization was
eradicated from seven of the 10 patients in whom this
was attempted, including patient no. 8. Eradication of
MRSA from these seven colonized patients may have
played an important role in controlling this outbreak.
The potential importance of eradicating colonization
may be best illustrated by the consequences of a delay
in attempting eradication for patient no. 8, one of the
colonized patients. This patient remained colonized
for 2 1/2 months before eradication was attempted and
was the only remaining reservoir for MRSA in the unit
for a period of 5 weeks. Had the eradication of MRSA
been begun earlier during hospitalization for patient
no. 8, it appears that the last five cases of the outbreak
could have been prevented, as well as the colonization
of two nurses and the occurrence of two more cases 5
months after the last case of the outbreak. Earlier
eradication of S. aureus in patient no. 8 would thus
have obviated the need for up to 6 months isolation
and weekly surveillance cultures and also for hundreds
of surveillance cultures of personnel.
The absence of detectable colonization among per-
sonnel during the outbreak suggests that patients rather
than health care workers served as the major reservoir
for transmission. Similar observations have been re-
corded in the majority of published MRSA outbreaks
(2, 10). Health care workers have been identified as a
reservoir of MRSA colonization in some reports, but
in a majority of these outbreaks, the implicated indi-
viduals had colonization of the hands or areas of
dermatitis rather than nasal colonization alone (2). A
nurse (Nurse A) apparently served as the reservoir for
transmission to two patients who became colonized
following the outbreak. This nurse, who was colonized
at the site of an eczematous hand lesion and groin, had
cared for these two patients after caring for the final
colonized infant of the outbreak 6 weeks earlier. Nurse
A had had negative cultures of the nares during the
outbreak and no visible lesions of eczema at that time.
Only two infants became colonized despite the fact
that Nurse A worked with multiple patients during the
6-week period following discharge of the last colo-
nized infant of the outbreak, perhaps due to use of
gloves and regular use of chlorhexidine handwash.
ACKNOWLEDGMENTS
This work was supported in part by National Institutes of
Health training grant no. T32AI07046.
The authors acknowledge the technical assistance pro-
vided by Lisa Durbin and clinical assistance provided by
Beth Sanderford.
Am J Epidemiol Vol. 143, No. 5, 1996
503
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