RESEARCH LETTERS

A Conflict of interest statement

Hazard ratio (95% CI) p A Jaffe is a consultant for and receives research support from Dade and
cTnT* 23·0 (10·8–48·8) <0·0001 Roche Diagnostics, and has given talks sponsored by both companies.
24 h M-spike† 1·60 (1·17–2·19) 0·004 W Miller receives research support from Roche Diagnostics.
Age‡ 1·27 (1·06–1·52) 0·009
Ejection fraction§ 1·39 (1·05–1·85) 0·020 Acknowledgments
100 Dade (DE, USA), and Roche (IN, USA), provided reagents for the
Score n MS (range months) second-generation and third-generation assays, respectively.
1 27 21·7 (7–119) R A Kyle’s and A Dispenzieri’s work was supported in part by grants
80 2 138 15·8 (<1–158) CA 62242 and CA 91561, respectively, from the National Cancer
3 81 3·2 (<1–87) Institute. The funding source had no role in study design, data
4 12 1·4 (<1–13) collection, data analysis, data interpretation, or writing of the report.
Survival (%)

60 5 3 < 1 (2–2·9)
1 Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and
40 p<0·0001 laboratory features in 474 cases. Semin Hematol 1995; 32: 45–59.
2 Apple FS, Wu AHB, Jaffe AS. European Society of Cardiology and
American College of Cardiology guidelines for redefinition of
20 myocardial infarction: how to use existing assays clinically and for
clinical trials. Am Heart J 2002; 144: 981–86.
3 Miller WL, Wright RS, McGregor CG, et al. Troponin levels in
0 patients with amyloid cardiomyopathy undergoing cardiac
transplantation. Am J Cardiol 2001; 88: 813–15.
4 Kyle RA, Greipp PR, O’Fallon WM. Primary systemic amyloidosis:
B Hazard ratio (95% CI) p multivariate analysis for prognostic factors in 168 cases. Blood 1986;
cTnI¶ 1·51 (1·15–1·98) 0·003 68: 220–24.
Ejection fraction§ 1·65 (1·25–2·18) 0·0004 5 Cueto-Garcia L, Reeder GS, Kyle RA, et al. Echocardiographic
Age‡ 1·26 (1·06–1·51) 0·01 findings in systemic amyloidosis: spectrum of cardiac involvement
24 h urine M protein† 1·35 (1·03–1·93) 0·03 and relation to survival. J Am Coll Cardiol 1985; 6: 737–43.
100 LV septal thickness|| 1·41 (1·03–1·78) 0·03
Divisions of Haematology and Internal Medicine (A Dispenzieri MD,
Score n MS (range months) R A Kyle MD, M A Gertz MD), Biostatistics (T M Therneau PHD),
80 1 44 16·5 (7–119)
Cardiovascular Diseases, and Internal Medicine (W L Miller MD,
2 178 11·1 (<1–158)
Survival (%)

39 2·2 (<1–37)
K Chandrasekaran MD, A S Jaffe MD), Laboratory Genetics
60 3
(J P McConnell PHD, A S Jaffe PhD), and Clinical Biochemistry and
Immunology (M F Burritt MD), Mayo Clinic, Rochester, MN 55905,
40 USA
p<0·0001
Correspondence to: Dr Angela Dispenzieri
20 (e-mail: dispenzieri.angela@mayo.edu)

0
0 20 40 60 80 100
Time (months)
cTnT (A) and cTnI (B) multivariate analysis of overall survival
in 261 patients with primary systemic amyloidosis
MS=median survival. A: Continuous risk score was calculated as: R=3·19
√cTnT+0·52 √urine M-spike+0·025 age+0·34 ejection fraction; where
cTnT and urine M-spike were the actual values in g/L and g per 24 h,
respectively; age was specified in years when less than 65, but for
patients 65 years and older, age was taken as 65; ejection fraction was
one (<55%) or zero (55%). Overall risk score ranged from 0·77 to 5·2.
B: The optimum multivariate prediction model, designed independently
for cTnI was R=0·399 cTnI+0·497 ejection fraction+0·0247 age+0·338
septal thickness+0·373 √urine M-spike. The assignment of values for the
variables is the same as for the cTnT model apart from: cTnI and septal
thickness variables were each assigned a value of one (0·1 g/L,
>15 mm, respectively) or zero (<0·1 g/L, 15 mm, respectively). The
maximum value of this risk score was 3·18. *Square root of cTnT in
mg/L. †Square root of urine M protein in g per 24 h. ‡Age=number of
years when less than 65, but 65 for all those older 65 years. §Ejection
fraction cut-off value of >55%. ¶cTnI <0·1 mg/L. ||Left-ventricular septal
thickness as a cut-off value of >15 mm.
myocyte damage. Measurement of troponin values could
provide useful information for clinicians, and might
potentially help to standardise risk comparisons.
120
CRIB II: an update of the clinical
risk index for babies score
Gareth Parry, Janet Tucker, William Tarnow-Mordi, for the UK
Neonatal Staffing Study Collaborative Group*
*See reference 2 for list of members
The clinical risk index for babies (CRIB) score is a risk-
adjustment instrument widely used in neonatal intensive care.
Its appropriateness with contemporary data has been
questioned. We have examined these questions, developed a
new five-item CRIB II score with data from a UK-wide sample of
infants admitted to neonatal intensive care in 1998–99, and
shown how mortality after neonatal intensive care has fallen in
the past 12 years. CRIB II provides a recalibrated and
simplified scoring system that avoids the potential problems of
early treatment bias. A valid and simple method of risk-
adjustment for neonatal intensive care is important to ensure
accurate assessment of quality of care. Such assessments
should be done in tandem with national audit systems for
neonatal intensive care, incorporating measures of morbidity as
well as mortality.

Contributors Lancet 2003; 361: 1789–91

A Dispenzieri, A Jaffe, W Miller, R Kyle, and M Gertz designed the
project. All investigators participated in constructive, critical review of
the manuscript. A Dispenzieri reviewed graphs and data, did preliminary
statistical analyses, and wrote the report. R Kyle supplied the stored
serum samples and the amyloid database. R Kyle and M Gertz were
resident experts for primary systemic amyloidosis, and A Jaffe for cardiac
troponins. T Therneau did the statistical modelling. K Chandrasekaran
reviewed the echocardiograms. J McConnell and M Burritt did the
troponin assays and verified their quality control.
The clinical risk index for babies (CRIB) score is a risk-
adjustment instrument used worldwide in neonatal
intensive care.1 It was developed with data relating to
babies born at less than 31 weeks’ gestation, or 1500 g
birthweight or lower, admitted for neonatal intensive care
between 1988 and 1990. The appropriateness of CRIB
with contemporary data has been questioned, since the

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS

Year Hosmer-Lemeshow Cox’s method

goodness of fit
Slope Constant
 df p z p Odds 95% CI z p Odds 95% CI
ratio ratio
CRIB 1988–90 51·6 9 <0·001 1·20 0·231 0·94 (0·86–1·04) 5·68 <0·001 0·56 (0·46–0·68)
1993–94 28·3 9 0·001 –0·67 0·504 1·03 (0·93–1·15) 2·56 0·001 0·75 (0·61–0·93)
Gestation 1988–90 334·0 9 <0·001 –7·73 <0·001 2·08 (1·72–2·50) 9·12 <0·001 0·44 (0·37–0·52)
1993–94 104·9 9 <0·001 –5·24 <0·001 1·49 (1·28–1·75) 2·88 <0·001 0·74 (0·60–0·91)
Birthweight 1988–90 197·0 10 <0·001 –2·31 0·021 1·19 (1·03–1·37) 10·27 <0·001 0·40 (0·34–0·48)
1993–94 95·8 10 <0·001 –2·31 0·021 1·19 (1·03–1·37) 5·19 <0·001 0·58 (0·48–0·71)
df=degrees of freedom.
Calibration of algorithms associated with CRIB, gestation, and birthweight to predict mortality in 1998–99 data
score may now be poorly calibrated with mortality after Neonatal Staffing Study excluded 34 deaths that might not
neonatal intensive care, in which case it might be no better reasonably be attributed to care in the neonatal unit. Such
in prediction of mortality than birthweight or gestation deaths were classified as due to lethal congenital
alone. Furthermore, CRIB includes, as one of two abnormalities or metabolic disorders, complex cardiac
measures of severity of illness, fraction of inspired oxygen surgery or organ transplantation, or as resuscitated
(FiO2), which is not a true physiological measure because it stillbirths.
is determined by the care team. CRIB also includes data up The available 1988–90 and 1993–94 algorithms for
to 12 h after admission, thus potentially introducing early conversion of CRIB into a probability of mortality were
treatment bias. poorly calibrated in the 1998–99 data, according to the
We investigated these issues with data from a nationally Hosmer-Lemeshow statistic (table). Cox’s method showed
representative sample of 3027 infants of 32 weeks’ that both the 1988–90 and 1993–94 CRIB algorithms
gestation or less, who were admitted to 54 UK units overpredicted mortality in 1998–99. The odds of mortality in
between March, 1998, and April, 1999, in the UK 1998–99 were 0·56 (95% CI 0·46–0·68) those of the
Neonatal Staffing Study.2 Their mean birthweight was 1355 1988–90, and 0·75 (0·61–0·93) those of the 1993–94
g (SD 443) and their median gestation was 30 weeks (IQR infants. Cox’s method showed that the available 1988–90
28–31). Mortality (death before hospital discharge) was and 1993–94 birthweight and gestation algorithms
240 (7·9%). Data were available for CRIB variables, overpredicted mortality, especially in infants of 26 weeks’
birthweight, and gestation, in 2971 (98·1%), 3026 gestation and more and with birthweight of 500 g and
(99·9%), and 3027 (100%) infants, respectively. The UK higher.

Birthweight (g) and gestation (weeks):

The maximum (worst) score for birthweight and gestation is 15, which is obtained for a 22 week male infant of less than 501 g birthweight
Male infants Female infants
2751 to 3000 0 2751 to 3000 0
2501 to 2750 1 0 2501 to 2750 1 0
2251to 2500 3 0 0 2251 to 2500 2 0 0
Birthweight (g)

Birthweight (g)

2001to 2250 2 0 0 2001 to 2250 1 0 0

1751to 2000 3 1 0 0 1751 to 2000 3 1 0 0
1501to 1750 6 5 3 2 1 0 1501 to 1750 6 4 3 1 0 0
1251to 1500 8 6 5 3 3 2 1 1251 to 1500 7 5 4 3 2 1 1
1001to 1250 12 10 9 8 7 6 5 4 3 3 1001 to 1250 11 10 8 7 6 5 4 3 3 3
751 to 1000 12 11 10 8 7 7 6 6 6 6 751 to 1000 11 10 9 8 7 6 5 5 5 5
501 to 750 14 13 12 11 10 9 8 8 8 8 501 to 750 13 12 11 10 9 8 8 7 7 7
251 to 500 15 14 13 12 11 10 10 251 to 500 14 13 12 11 10 10 10
22 23 24 25 26 27 28 29 30 31 32 22 23 24 25 26 27 28 29 30 31 32
Gestation (weeks) Gestation (weeks)

Temperature at admission (˚C) Base excess (mmol/L):

29·6 5
26 7
29·7 to 31·2 4
26 to
23 6
31·3 to 32·8 3
22 to
18 5
32·9 to 34·4 2
17 to
13 4
34·5 to 36 1
12 to
8 3
36·1 to 37·5 0
7 to
3 2
37·6 to 39·1 1
2 to 2 1
39·2 to 40·7 2 3 0
40·8 3

Sex, birthweight (g) and gestation (weeks):

Temperature at admission (˚C):
Base excess (mmol/L):

Total CRIB II Score

The logistic regression equation relating CRIB II to mortality (CRIB II algorithm) is:
Log odds of mortality = G =
6·476 + 0·450CRIB II
Probability of mortality = exp(G)/[1+exp(G)]
The range of possible CRIB II scores is 0 to 27

Clinical risk index for babies II (CRIB II) score

1790 THE LANCET • Vol 361 • May 24, 2003 • www.thelancet.com

For personal use. Only reproduce with permission from The Lancet Publishing Group.

As an extension of work by Draper and co-workers (a grid
of probabilities of mortality by birthweight, gestation, and
sex)3 we developed and assessed CRIB II for infants of
32 weeks’ gestation, with further data available up to 1 h
after admission to neonatal intensive care, excluding FiO2.
To develop this instrument, we used data relating to a group
of 1886 infants consecutively admitted to 35 randomly
selected neonatal intensive care units contributing to the
UK Neonatal Staffing Study.
We fitted log-odds derived from the Draper Grid by use
of logistic regression with mortality as the outcome. We
then added other available variables relating to the period
up to 1 h after admission. Candidate variables identified by
the UK Neonatal Staffing Study Steering Group were:
mode of delivery, temperature at admission, surfactant
treatment, blood pH, SaO2, PaCO2, PaO2, and HCO3, and
diagnostic severity categories (established and validated by a
panel of eight specialists in neonatal medicine). We used the
Akaike information criteria to identify the best model
including birthweight, gestation, sex, admission
temperature, and base excess, and the coefficients of the
final model were rounded to form CRIB II (figure).
Application of CRIB II to the assessment group (1065
infants admitted to the remaining 19 units) gave a receiver-
operating-characteristic area of 0·92 (SE 0·01). Both the
Hosmer-Lemeshow goodness of fit test (2=4·30, 8 df,
p=0·829) and Cox’s assessment (slope p=0·642 and
constant p=0·141) showed adequate calibration.
We had shown no difference in CRIB-adjusted mortality
for infants of 32 weeks’ gestation or less between large and
small neonatal intensive care units (odds ratio 1·19, 95% CI
0·70–2·02) with the UK Neonatal Staffing Study data. We
repeated this test with CRIB II, and found that CRIB II-
adjusted mortality did not differ between large and small
units (odds ratio 1·06, 95% CI 0·70–1·60). Thus similar
results were obtained with CRIB on the basis of information
up to 12 h after admission, and with CRIB II on the basis of
information up to 1 h after admission.
When we assessed CRIB II in relation to death or major
cerebral abnormality (cystic leucomalacia or porencephalic
cyst on cranial ultrasound, arising more than 10 days after
birth) in the assessment group, CRIB II gave a receiver-
operating-characteristic area of 0·82 (SE 0·02). This area
was significantly higher than those of 0·79 (0·02) for CRIB,
0·80 (0·02) for gestation, 0·77 (0·02) for birthweight, and
0·80 (0·02) for the Draper grid.
Available 1988–90 and 1993–94 CRIB algorithms were
poorly calibrated for data from 1998–99. CRIB II provides a
recalibrated and simplified scoring system, which avoids the
potential problems associated with use of FiO2 and data up to
12 h after admission. Although this difference might be due
to participation of different units in the different time
periods, our findings of falling hospital mortality since 1988
are similar to those of other studies.4 This fall could be
attributable to increasing clinical expertise, the introduction
of surfactant treatment from the late 1980s, and the growing
use of antenatal steroids from the early 1990s. Future
investigations should assess the effect on health outcomes
over time of improved clinical skills, increased uptake of
effective treatments, and improved service organisation.5
Before falling mortality can be judged a health gain,
information about the long-term health of neonatal intensive
care survivors should be routinely assessed.4 Future
investigations of neonatal intensive care need not only the
benchmark information presented here, but also appropriate
risk-adjustment instruments such as CRIB II, and valid
morbidity outcomes as measurement of quality and
performance. This is achievable through the introduction of
a national neonatal intensive care audit system.
THE LANCET • Vol 361 • May 24, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Participating neonatal intensive care units
Airedale General Hospital, Keighley; Antrim Hospital, Antrim; Arrowe
Park Hospital, Upton; Birch Hill Hospital, Rochdale; Burnley General
Hospital, Burnley; City Hospital Birmingham, Birmingham; Derby City
Hospital NHS Trust, Derby; Dewsbury District Hospital, Dewsbury;
Erne Hospital, Enniskillen; Fairfield General Hospital, Bury;
Farnborough Hospital, Orpington; Gloucestershire Royal Hospital,
Gloucestershire; Good Hope Hospital, Sutton Coldfield; Greenwich
Healthcare Trust, London; Grimsby Maternity Hospital, Grimsby;
Hereford County Hospital, Hereford; Huddersfield Royal Infirmary,
Huddersfield; Jersey Maternity Hospital, St Helier; Kent and Canterbury
Hospital, Canterbury; Kettering General Hospital, Kettering; King’s Mill
Hospital, Sutton-In-Ashfield; Norfolk and Norwich Hospital, Norwich;
North Devon District Hospital, Barnstaple; Northampton General
Hospital, Northampton; Northern General Hospital Sheffield, Sheffield;
Northwick Park Hospital, Harrow; Nottingham University Hospital,
Nottingham; Peterborough District Hospital, Peterborough; Prince
Charles Hospital, Merthyr Tydfil; Queen Elizabeth Hospital Gateshead,
Gateshead; Rotherham District General Hospital, Rotherham; Royal
Alexandra Hospital, Brighton; Royal Devon and Exeter Hospital, Exeter;
Royal Hampshire County Hospital, Winchester; Royal Oldham Hospital,
Oldham; Royal Preston Hospital, Preston; Royal Surrey County Hospital,
Guilford; Royal United Hospital, Bath; Salisbury NHS Trust, Salisbury;
Scunthorpe General Hospital, Scunthorpe; South Cleveland Hospital,
Middlesbrough; South End Hospital, South End; Southern General
Hospital, Glasgow; St George’s Hospital, London; St Mary’s Hospital,
Portsmouth; St Paul’s Hospital, Cheltenham; St Peter’s Hospital,
Chertsey; St Thomas’ Hospital, London; Stoke Mandeville Hospital,
Aylesbury; The Ipswich Hospital NHS Trust, Ipswich; William Harvey
Hospital, Ashford; Wordsley Hospital, Stourbridge; Wycombe General
Hospital, High Wycombe; York District Hospital, York.
Contributors
G Parry planned and undertook the analysis, and contributed to the
writing of the paper. J Tucker and W Tarnow-Mordi reviewed the analysis
plan and results, and contributed to the writing of the paper.
Conflict of interest statement
None declared.
Acknowledgments
We thank all UK neonatal units and staff for their support. We thank
link audit nurses, nurse managers, and clinicians who obtained
prospective data on our behalf. We also wish to acknowledge the huge
contributions of the late Douglas Richardson for his efforts in the
promotion of risk adjustment and assessment of improvements in
neonatal intensive care worldwide. The views expressed in this paper are
those of the authors. This study was funded by the NHS R&D
Executive, Mother and Child Health Programme (grant number
MCH:6-7) and the Department of Health, UK. The funding source had
no role in study design, data collection, data analysis, data
interpretation, or writing of the report.
1 The International Neonatal Network. The CRIB (clinical risk index
for babies) score: a tool for assessing initial neonatal risk and
comparing performance of neonatal intensive care units. Lancet
1993; 342: 193–98.
2 UK Neonatal Staffing Study Group. Patient volume, staffing and
workload in relation to risk-adjusted outcomes in a random stratified
sample of UK neonatal intensive care units: a prospective evaluation.
Lancet 2002; 359: 99–107
3 Draper ES, Manktelow B, Field D, James D. Prediction of survival
for preterm births by weight and gestational age: retrospective
population based study. BMJ 1999; 319: 1093–97
4 Richardson DK, Gray JE, Gortmaker SL, Goldman DA, Pursley
DM. McCormick MC. Declining severity adjusted mortality:
evidence of improving neonatal care. Pediatrics 1998; 102: 893–99
5 Halm EA, Chassin MR. Why do hospital death rates vary?
N Engl J Med 2001; 345: 692–94
Medical Care Research Unit, School of Health and Related
Research, University of Sheffield, Regent Court, 30 Regent Street,
Sheffield S1 4DA, UK (G Parry PhD); Dugland Baird Centre for
Research on Women’s Health, Department of Obstetrics and
Gynaecology, University of Aberdeen, Aberdeen, UK (J Tucker PhD);
Westmead and Children’s Hospital at Westmead, University of
Sydney, Sydney, Australia (W Tarnow-Mordi MRCP)
Correspondence to: Dr Gareth Parry
(e-mail: g.parry@sheffield.ac.uk)
1791