Nutritional Benefits of Neonatal Screening for Cystic Fibrosis
Philip M. Farrell, M.D., Ph.D., Michael R. Kosorok, Ph.D., Anita Laxova, B.S., Guanghong Shen, M.S., Rebecca E. Koscik, M.S., W. Theodore Bruns, M.D., Mark Splaingard, M.D., Elaine H. Mischler, M.D., for The Wisconsin Cystic Fibrosis Neonatal Screening Study Group
Background Many patients with cystic fibrosis are malnourishedat the time of diagnosis. Whether newborn screening and earlytreatment may prevent the development of a nutritional deficiencyis not known.
Methods We compared the nutritional status of patients withcystic fibrosis identified by neonatal screening or by standarddiagnostic methods. A total of 650,341 newborn infants werescreened by measuring immunoreactive trypsinogen on dried bloodspots (from April 1985 through June 1991) or by combining thetrypsinogen test with DNA analysis (from July 1991 through June1994). Of 325,171 infants assigned to an early-diagnosis group,cystic fibrosis was diagnosed in 74 infants, including 5 withnegative screening tests. Excluding infants with meconium ileus,we evaluated nutritional status for up to 10 years by anthropometricand biochemical methods in 56 of the infants who received anearly diagnosis and in 40 of the infants in whom the diagnosiswas made by standard methods (the control group). Pancreaticinsufficiency was managed with nutritional interventions thatincluded high-calorie diets, pancreatic-enzyme therapy, andfat-soluble vitamin supplements.
Results The diagnosis of cystic fibrosis was confirmed by apositive sweat test at a younger age in the early-diagnosisgroup than in the control group (mean age, 12 vs. 72 weeks).At the time of diagnosis, the early-diagnosis group had significantlyhigher height and weight percentiles and a higher head-circumferencepercentile (52nd, vs. 32nd in the control group; P = 0.003).The early-diagnosis group also had significantly higher anthropometricindexes during the follow-up period, especially the childrenwith pancreatic insufficiency and those who were homozygousfor the F508 mutation.
Conclusions Neonatal screening provides the opportunity to preventmalnutrition in infants with cystic fibrosis.
Cystic fibrosis, one of the most common life-threatening autosomalrecessive disorders, can be difficult to diagnose, and its recognitionis therefore often delayed. In 1995, the mean age at the timeof diagnosis was 2.9 years in the United States.1 At the timeof diagnosis, many patients are malnourished or have chroniclung disease,2,3 and some have hypoproteinemia with edema (acutekwashiorkor), vitamin E deficiency with hemolytic anemia, orsevere hyponatremia, hypochloremia, and dehydration.4,5,6 Infact, a recent analysis of data from the National Cystic FibrosisFoundation Registry showed that 44 percent of the patients whoreceived a diagnosis of cystic fibrosis in 1993 had malnutritionsevere enough to cause either wasting of body mass or stuntingof growth.7
The potential nutritional advantages of early diagnosis ledShwachman et al.8 to recommend neonatal screening for cysticfibrosis in 1970. Screening based on meconium analysis was unsuccessful,but the detection of low values of trypsinogen in dried bloodspecimens obtained in routine screening programs for metabolicdisorders proved effective for this purpose.9 Subsequent studiesconfirmed the usefulness of trypsinogen testing,10 and its efficacyhas been improved with a two-step approach in which the trypsinogenassay is followed by an analysis of DNA for mutations in thegene for the cystic fibrosis transmembrane regulator.11 Beforeroutine neonatal screening for cystic fibrosis can be recommended,however, the efficacy of early diagnosis must be establishedby demonstrating that the benefits outweigh the potential risksand justify the costs of screening.12 In 1985, a comprehensiveevaluation of neonatal screening for cystic fibrosis was implementedin Wisconsin to determine the optimal screening strategy andto assess the benefits, risks, and costs of screening. A descriptionof the screening tests,13 their costs,14 and the potential risksof screening15 have been reported elsewhere. To investigatethe potential benefits of screening, we have chosen nutritionalfactors and pulmonary disease as outcome measures. The analysisof pulmonary outcomes will continue until 1999. We report hereon the nutritional benefits of neonatal screening for cysticfibrosis.
Methods
Study Design
The design of the study has been described in detail elsewhere.16To summarize, we performed a randomized investigation of neonatalscreening for cystic fibrosis in two concurrent groups of infantsfollowed prospectively with the use of the same protocol. Sequentialcomparisons were made between a group of infants who receivedan early diagnosis through neonatal screening and a controlgroup identified by other means. All the infants were screenedwith the use of trypsinogen testing of blood spots obtainedfor routine neonatal screening (between April 15, 1985, andJune 30, 1991) or trypsinogen testing followed, in the caseof abnormal results, by analysis of DNA for the F508 mutantallele (between July 1, 1991, and June 30, 1994). Only the infantswhose blood-specimen numbers ended in an odd digit were recalledfor sweat testing if the results of the trypsinogen or trypsinogen–DNAtests were abnormal (the early-diagnosis group). Trypsinogenwas measured by a radioimmunoassay with the use of the Sorinmethod.10,11 The F508 mutation was identified with the use ofallele-specific oligonucleotides after polyacrylamide-gel electrophoresisof DNA digests amplified by the polymerase chain reaction.12,13The children in the control group were identified on the basisof the presence at birth of meconium ileus, which usually leadsto a rapid diagnosis; a family history of cystic fibrosis; thedevelopment of symptoms or signs of cystic fibrosis, leadingto a sweat test before four years of age; or positive resultson neonatal trypsinogen or trypsinogen–DNA testing, revealedon unblinding of the data when the children were four yearsold.16 We could therefore identify all children with cysticfibrosis by four years of age.
Once a diagnosis of cystic fibrosis was confirmed by a positivesweat test (sweat chloride concentration, 60 mmol per literor higher), the patient was followed every three months untilthe age of 10 years. Follow-up assessments included anthropometricand biochemical measurements of nutritional status and evaluationof the clinical severity of disease according to the Shwachman–Kulczyckimethod.17 All follow-up assessments were performed at the MadisonCystic Fibrosis Center (University of Wisconsin) or the MilwaukeeCystic Fibrosis Center (Medical College of Wisconsin). All patientswere treated according to a protocol that specified interventionsfor nutritional deficiencies and pulmonary disease.18 Nutritionaltherapy for patients with pancreatic insufficiency includedhigh-calorie diets and supplementation with pancreatic enzymesand fat-soluble vitamins.
The study was approved by the human subjects committee at theUniversity of Wisconsin and the research and publications committeeand human rights board at Children's Hospital of Wisconsin.The children's parents gave informed consent.
Nutritional Assessments
The starting point for the nutritional assessments was the dateof a positive sweat test at one of the participating centers.At each visit, a research nurse or dietitian measured the child'slength or height and weight. The child's recumbent length, tothe nearest 0.5 cm, was measured with the use of a calibratedwooden board. After two years of age, height was measured witha stadiometer. For infants, weight was determined to within0.1 kg, with the child placed in the center of a balance-scaleplatform and wearing minimal clothing and no diaper. Weight-for-age,length-for-age, and weight-for-length percentiles were calculatedwith the use of growth charts from the National Center for HealthStatistics and the EpiInfo software program.19 In addition,deviations of the anthropometric measurements from the growth-chartreference medians were determined by the standardized z-scoretechnique.
Blood was obtained every six months for measurement of plasmavitamins A and E by high-performance liquid chromatography.20At a mean age of four years, the children were classified accordingto their pancreatic function on the basis of three-day fat-absorptionstudies, whenever possible, and a new classification methoddeveloped with the use of our fat-absorption data and informationfrom previous studies.21,22,23 With the new method, pancreaticfunction was classified according to the plasma concentrationsof vitamin E (normal value for -tocopherol, >500 µgper deciliter [11.5 µmol per liter]; normal value for-tocopherol or -tocopherol, >180 µg per deciliter [4.1µmol per liter]) and vitamin A (normal value, >20 µgper deciliter [0.7 µmol per liter]) and the blood trypsinogenconcentration. If at least two of the three values were normalor unchanged, the patient was classified as having probablepancreatic sufficiency; otherwise, the patient was classifiedas having probable pancreatic insufficiency. This method wasvalidated with the use of data from the patients who underwentfat-absorption studies; 91 percent accuracy was achieved withthe three blood tests.
Statistical Analysis
We used the method of Wei et al.24 to assess the effect of screening,with adjustments for stratification variables and multiple interimanalyses.25 We performed a repeated-measures analysis usinggeneralized-estimating-equation methods with a working assumptionof independence among observations26,27 to assess the differencesin anthropometric indexes between the early-diagnosis groupand the control group. The analyses were adjusted for age, sex,center, genotype, pancreatic status, and age at diagnosis. Interactionterms for sex and other covariates were also included in theregression models to determine whether the differences betweenthe groups were due to sex. Because there was a 5 percent differencein birth weight between the two groups, we reassessed the overalldifferences in nutritional outcomes between the groups by addingthe birth-weight percentile as a covariate in the repeated-measuresanalyses. The validity of these models was assessed by examiningnormal quantile–quantile plots of residuals as well asplots of residuals versus fitted values.28 Other statisticalmethods included the Wilcoxon rank-sum test for continuous variablesand Fisher's exact test for categorical variables (both usedas two-sided tests).
Results
Between April 15, 1985, and June 30, 1994, a total of 650,341infants were screened for cystic fibrosis during the first 28days of life. Screening during the neonatal period led to thediagnosis of cystic fibrosis in 54 infants. Fifteen infantsin the early-diagnosis group had meconium ileus, and 5 otherinfants had false negative screening tests and were identifiedbecause of either a family history (2 infants) or symptoms ofcystic fibrosis (3 infants). The control group included 67 infantsor children, 18 of whom had meconium ileus and 9 of whom hadpositive results on sweat testing performed at the age of fouryears because of a positive neonatal screening test. Becausethe presence of meconium ileus led to an early diagnosis routinelyin both groups and in view of the fundamental principle29 thatscreening involves the use of a test to identify people whoare still asymptomatic,30 our nutritional study was focusedon patients who had cystic fibrosis without meconium ileus.All reported results refer to the patients without meconiumileus. Fifty-six patients assigned to the early-diagnosis groupand 40 assigned to the control group were enrolled in the study(Figure 1).
Figure 1. Identification and Enrollment of Patients with Cystic Fibrosis.
Patients were assigned to the early-diagnosis group if the identification number for the neonatal blood specimen ended in an odd digit and to the standard-diagnosis (control) group if it ended in an even digit. Screening was performed with the trypsinogen test (87 percent sensitivity, 100 percent specificity) or the trypsinogen test combined with DNA analysis (100 percent sensitivity, 100 percent specificity).13 Of the five patients with false negative trypsinogen tests in the early-diagnosis group, two were identified because of a family history, and three because of symptoms of cystic fibrosis. The patients in the control group were identified on the basis of a family history of cystic fibrosis or symptoms or signs of the disease (usually malabsorption or respiratory disease), meconium ileus (MI) leading to a sweat test, or the unblinding of neonatal data when the child reached four years of age. The diagnosis of cystic fibrosis required a sweat chloride concentration of 60 mmol per liter or higher. Patients with meconium ileus were excluded from the analysis.
The demographic and genetic characteristics of the two groupsof patients without meconium ileus are shown in Table 1. Therewas a significant difference in the age at diagnosis, with amean of 12 weeks in the early-diagnosis group as compared with72 weeks in the control group (P = 0.001). The age at the timeof diagnosis in the control group did not differ significantlyfrom that of the 35 consecutive children with cystic fibrosisdiagnosed at the Madison Cystic Fibrosis Center before the screeningtrial (mean, 73 weeks; median, 36 weeks). There were no significantdifferences in sex or center distribution between the two groups;however, more patients in the early-diagnosis group had theF508 mutation. The two groups also differed with regard to pancreaticfunctional status, but the overall frequency of pancreatic insufficiency(83 percent) was similar to that reported in other studies ofyoung children with cystic fibrosis.21,31,32
Table 1. Demographic, Nutritional, and Clinical Characteristics at the Time of Diagnosis of Cystic Fibrosis in Patients without Meconium Ileus.
At the time of diagnosis, the length or height, weight, andhead-circumference percentiles in the early-diagnosis groupwere significantly higher than those in the control group (Table 1).The mean growth-and-nutrition component of the Shwachman–Kulczyckiscore and the total score were also significantly higher inthe early-diagnosis group. Plasma vitamin E concentrations werelow in 71 percent of the early-diagnosis group and 57 percentof the control group (P = 0.25), and plasma vitamin A (retinol)concentrations were low (<20 µg per deciliter [0.7µmolper liter]) in 36 percent and 29 percent, respectively (P =0.49); the mean values for vitamins A and E in the two groupswere similar. The differences in growth indexes at the timeof diagnosis were of such magnitude that we obtained data onbirth weight retrospectively and found that the mean (±SD)weight was higher in the early-diagnosis group than in the controlgroup (3.37±0.37 kg [59±26 percentile] vs. 3.19±0.57kg [45±32 percentile]) (P = 0.03).
Overall, during the 10-year follow-up period, the weight andheight were higher in the early-diagnosis group than in thecontrol group. Specifically, the early-diagnosis group had significantlyhigher weight-for-age (P = 0.04) and height-for-age (P = 0.02)percentiles (data not shown) and higher z scores for weight(P = 0.04) and height (P = 0.02) than the control group (Figure 2).After adjustment for the difference in birth weight, thechildren in the early-diagnosis group were still heavier andtaller than those in the control group, but the only differencesbetween the groups that remained significant during follow-upwere the height-for-age percentile (P = 0.04) and the z score(P = 0.02). When height or weight below the 10th percentilewas used as an index of severe malnutrition,7 the outcome wasalso significantly better in the early-diagnosis group. Theodds ratio for the risk of a weight below the 10th percentilein the control group, as compared with the early-diagnosis group,was 3.1 (95 percent confidence interval, 1.3 to 7.2), and thecorresponding odds ratio for height was 3.5 (95 percent confidenceinterval, 1.3 to 9.7). Neonatal screening reduced the risk ofa height below the 10th percentile throughout the first 10 yearsof life, with no overlap in values between the two groups (Figure 3).
Figure 2. Anthropometric Indexes in Relation to Age in the Early-Diagnosis and Control Groups, Standardized According to z Scores.
There were 294 observations each for weight and height in the early-diagnosis group and 187 each in the control group; the number of observations ranged from 4 (at 10 years) to 52 (at 1 year) in the early-diagnosis group and from 9 (at 10 years) to 26 (at 1 year) in the control group. Overall, during the 10-year study period, there were significant differences between the two groups in the z scores for both weight (P = 0.04) and height (P = 0.02), by repeated-measures analyses. There were also significant differences in the z score for weight at one year (P = 0.005) and height at one year (P = 0.002) and two years (P = 0.01).
Figure 3. Proportions of Patients in the Early-Diagnosis and Control Groups Whose Weight or Height Were below the 10th Percentile at the Annual Assessment.
Both weight and height percentiles were significantly higher in the early-diagnosis group than in the control group. The numbers of observations are given in the legend for Figure 2.
There were no significant differences in weight and height percentilesaccording to the sex of the patients, but there was significantvariation associated with pancreatic function and genotype (Table 2).Among the patients with pancreatic sufficiency, there wereno significant differences in weight or height at the time ofdiagnosis or at one year, but among those with pancreatic insufficiency,the patients in the early-diagnosis group were heavier and tallerthan those in the control group until the age of five years.Among the patients who were homozygous for the F508 mutation,those in the early-diagnosis group were at significantly higherweight and height percentiles than those in the control groupat the time of diagnosis and at one year (Table 2).
Table 2. Weight and Height Percentiles According to Pancreatic Status and Genotype.
Discussion
Multiple factors influence the nutritional status of patientswith cystic fibrosis, including pancreatic function, genotype,diet, eating behavior, nutritional supplements, severity oflung disease, and possibly age at the time of diagnosis.7,32,33,34,35We evaluated the role of age at the time of diagnosis by studyingthe nutritional status of patients with cystic fibrosis whowere enrolled in our neonatal screening study. We found thatthe patients in whom cystic fibrosis was detected by screeningwere heavier and longer and had a larger head circumferencethan those in whom the disorder was diagnosed on the basis ofa family history, illness, or testing at four years becauseof high blood trypsinogen concentrations at birth. Althoughthe greater weight of children in the early-diagnosis groupmay be attributable in part to the 5 percent higher birth weightin this group, the nearly twofold higher mean weight percentileand consistently higher length or height percentile in the early-diagnosisgroup are clinically important findings. The differences associatedwith screening were especially marked in the subgroups of patientswith cystic fibrosis who had pancreatic insufficiency or theF508/F508 genotype. Such patients are known to have the mostsevere disease.31,35 Thus, we conclude that age at the timeof diagnosis is an important factor in the nutritional statusof patients with cystic fibrosis and associated pancreatic insufficiency.
Questions have arisen about whether our neonatal screening studyresulted in an earlier diagnosis of cystic fibrosis by standardmethods in Wisconsin during the study period. The mean age atthe time of diagnosis in the members of the control group, whowere identified between 1985 and 1994, was almost identicalto that of children in whom the diagnosis was made before thestudy (72 and 73 weeks, respectively). In addition, the ageat the time of diagnosis in the control group did not differsignificantly from that of patients in the National Cystic FibrosisFoundation Registry.7 Furthermore, our control (standard-diagnosis)group resembles the registry group in terms of height and weight.7Thus, our control group is representative of the U.S. populationof patients with cystic fibrosis.
Our longitudinal assessments showed that the early-diagnosisgroup had significantly higher height and weight percentilesand z scores not only at the time of diagnosis but also duringthe 10-year follow-up period. The differences, however, diminishedwith time, and the convergence of the values for the two groupsby five to six years of age probably reflects the effects ofnutritional therapy, because nearly all patients identifiedclinically through symptoms and signs received the diagnosisby four years of age and were given aggressive treatment, aswere those recalled at the age of four years because of a positivescreening test. Nevertheless, there was no overlap or crossoverin values for height throughout the trial. Consequently, thenutritional-status component of this investigation should beregarded as demonstrating a positive effect of both neonatalscreening and nutritional therapy. We conclude that a delayeddiagnosis of cystic fibrosis increases the risk of malnutritionin childhood. We also conclude that early initiation of comprehensivenutritional therapy prevents malnutrition in children with pancreaticinsufficiency. The essential components of nutritional managementare a high-calorie diet and supplementation with pancreaticenzymes and fat-soluble vitamins.20,21,35
The characteristics of screening tests for cystic fibrosis havebeen studied thoroughly.11,13,36,37 Neonatal screening withthe trypsinogen test and DNA analysis is preferable, in ourjudgment, to screening with the trypsinogen test alone.13,37The advantages of the combined method include higher sensitivity,a higher positive predictive value, fewer false positive tests,a more rapid diagnosis with no need for repeated testing, andthe identification of heterozygous carriers, which permits geneticcounseling.13 In addition, the cost per patient identified isno greater with the combined method.14 In 1992, the estimatedcost of diagnosis was $11,377 per patient with the standardsweat test, $7,613 with the trypsinogen test, and $7,403 withthe combined trypsinogen–DNA method. In 1995, when weimplemented combined testing as a statewide service, the costwas $10,150 per patient identified. In fact, the laboratorycosts for trypsinogen–DNA testing for cystic fibrosisare similar to the costs of tests for phenylketonuria, and thepositive predictive value of trypsinogen–DNA testing ishigher.11,37 Our economic analyses suggest that cost will notbe the determining factor in deciding how to perform neonatalscreening for cystic fibrosis. Rather, the question should bebased on an analysis of the relation between benefits and risks.With regard to the risks, in nearly 10 years of investigatingneonatal screening for cystic fibrosis, we have not identifiedany long-term adverse effects. With regard to the benefits,data from uncontrolled studies suggest that patients identifiedthrough neonatal screening subsequently have less severe lungdisease than those identified by other means,36,38 but morecompelling evidence of the long-term pulmonary benefits is required.On the basis of our data, it is clear that early diagnosis throughneonatal screening has nutritional benefits, as evidenced bybetter growth. Neonatal screening for cystic fibrosis providesan important opportunity to prevent malnutrition in many patients.
Supported by grants from the National Institutes of Health (DK34108 and RR03186) and the Cystic Fibrosis Foundation (A0015-01).
* Other members of the Wisconsin Cystic Fibrosis Neonatal ScreeningStudy Group are listed in the Appendix.
Source Information
From the Department of Pediatrics and Biostatistics, University of Wisconsin, Madison (P.M.F., M.R.K., A.L., G.S., R.E.K.), and the Department of Pediatrics, Medical College of Wisconsin, Milwaukee (W.T.B., M.S., E.H.M.).
Address reprint requests to Dr. Farrell at the University of Wisconsin Medical School, 1300 University Ave., Madison, WI 53706.
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Appendix
In addition to the authors, the following investigators participatedin the Wisconsin Cystic Fibrosis Neonatal Screening Study Group:University of Wisconsin, Madison, Medical School, Madison —C. Green, M. Palta, M.J. Rock, A. Tluczek, M. Block, L.A. Davis,L. Feenan, L.J. Wei, and B.S. Wilfond; Medical College of Wisconsin,Milwaukee — H. Colby, W. Gershan, C. McCarthy, L. Rusakow,and M.E. Freeman; and Wisconsin State Laboratory of Hygiene,Madison — G. Hoffman, D.J. Hassemer, and R.H. Laessig.
Stafler, P., Wallis, C.
(2009). Extra corporeal membrane oxygenation (ECMO) therapy in a 3-year-old child with cystic fibrosis: a tale of hope. JRSM
102: 54-58
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Lai, H. J., Shoff, S. M., Farrell, P. M., with the Wisconsin Cystic Fibrosis Neonatal Screen,
(2009). Recovery of Birth Weight z Score Within 2 Years of Diagnosis Is Positively Associated With Pulmonary Status at 6 Years of Age in Children With Cystic Fibrosis. Pediatrics
123: 714-722
[Abstract][Full Text]
Kloosterboer, M., Hoffman, G., Rock, M., Gershan, W., Laxova, A., Li, Z., Farrell, P. M.
(2009). Clarification of Laboratory and Clinical Variables That Influence Cystic Fibrosis Newborn Screening With Initial Analysis of Immunoreactive Trypsinogen. Pediatrics
123: e338-e346
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Kremer, T. M., Zwerdling, R. G., Michelson, P. H., O'Sullivan, B. P.
(2008). Intensive Care Management of the Patient With Cystic Fibrosis. J Intensive Care Med
23: 159-177
[Abstract]
Balfour-Lynn, I. M
(2008). Newborn screening for cystic fibrosis: evidence for benefit. Arch. Dis. Child.
93: 7-10
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Bishop Hubbard, H.
(2007). Policy Issues Related to Expanded Newborn Screening: A Review of Three Genetic/Metabolic Disorders. Policy Politics Nursing Practice
8: 201-209
[Abstract]
Mayer-Hamblett, N., Ramsey, B. W., Kronmal, R. A.
(2007). Advancing Outcome Measures for the New Era of Drug Development in Cystic Fibrosis. Proc Am Thorac Soc
4: 370-377
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Bell, S. C, Robinson, P. J
(2007). Exacerbations in cystic fibrosis: 2 {middle dot} Prevention. Thorax
62: 723-732
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Padman, R., McColley, S. A., Miller, D. P., Konstan, M. W., Morgan, W. J., Schechter, M. S., Ren, C. L., Wagener, J. S., for the Investigators and Coordinators of the Epid,
(2007). Infant Care Patterns at Epidemiologic Study of Cystic Fibrosis Sites That Achieve Superior Childhood Lung Function. Pediatrics
119: e531-e537
[Abstract][Full Text]
Sims, E. J., Clark, A., McCormick, J., Mehta, G., Connett, G., Mehta, A., on behalf of the United Kingdom Cystic Fibrosis Da,
(2007). Cystic Fibrosis Diagnosed After 2 Months of Age Leads to Worse Outcomes and Requires More Therapy. Pediatrics
119: 19-28
[Abstract][Full Text]
Sawyer, S. M., Cerritelli, B., Carter, L. S., Cooke, M., Glazner, J. A., Massie, J.
(2006). Changing Their Minds With Time: A Comparison of Hypothetical and Actual Reproductive Behaviors in Parents of Children With Cystic Fibrosis. Pediatrics
118: e649-e656
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Shoff, S. M., Ahn, H.-Y., Davis, L., Lai, H., the Wisconsin CF Neonatal Screening Group,
(2006). Temporal Associations Among Energy Intake, Plasma Linoleic Acid, and Growth Improvement in Response to Treatment Initiation After Diagnosis of Cystic Fibrosis. Pediatrics
117: 391-400
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Corech, R., Rao, A., Laxova, A., Moss, J., Rock, M. J., Li, Z., Kosorok, M. R., Splaingard, M. L., Farrell, P. M., Barbieri, J. T.
(2005). Early Immune Response to the Components of the Type III System of Pseudomonas aeruginosa in Children with Cystic Fibrosis. J. Clin. Microbiol.
43: 3956-3962
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(2005). Diagnosis and management of cystic fibrosis. EDUCATION AND PRACTICE
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F508 mutation. 
-tocopherol, >500 µg per deciliter [11.5 µmol per liter]; normal value for 
-tocopherol or 
-tocopherol, >180 µg per deciliter [4.1 µmol per liter]) and vitamin A (normal value, >20 µg per deciliter [0.7 µmol per liter]) and the blood trypsinogen concentration. If at least two of the three values were normal or unchanged, the patient was classified as having probable pancreatic sufficiency; otherwise, the patient was classified as having probable pancreatic insufficiency. This method was validated with the use of data from the patients who underwent fat-absorption studies; 91 percent accuracy was achieved with the three blood tests. 
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