What is the sensitivity and specificity of amniotic fluid

lamellar body count in detection of respiratory distress syndrome?

Faculdade de Medicina da Universidade do Porto

Turma 9

IntroductionWhat is the aim of this study?What is a respiratory distress

syndrome?What is a test's sensitivity and

specificity?

Why is this meta-analysis important?

What is the aim of this study?

The aim of our study is a meta-analysis of the articles that

evaluate the specificity and sensitivity of amniotic fluid

lamellar body count (LBC) in detection of respiratory distress

syndrome (RDS), providing by this mean reliable information

to all health personnel about this test.

What is a respiratory distress syndrome?

RDS: Frequent in premature infants, children of diabetic

mothers and infants delivered by caesarean section;

Syndrome of respiratory difficulty caused by a deficiency of lung surfactant;

Symptoms: dyspnoea with cyanosis dilatation of the alae nasi expiratory grunt etc.

Possible treatments : extra oxygen(21%)

CPAP (Continuous Positive Airway Pressure),

surfactant

In last case the baby is intubated

CUNNINGHAM, F.Gary et al ;William’s Obstetrics;22nd edition; Mc Graw-Hill; Medical Publishing Division; New York www.pedriatics.wisc.edu

RDS remains a common cause of neonatal morbidity and mortality.

Consequently fetal lung maturity (FLM) testing plays an important role in establishing obstetric management strategies

several biophysical and biochemical laboratory tests were developed

the most widely used are Lecithin toSphingomyelin (L/S) ratio and the quantification of phosphatidylglycerol (PG) in amniotic fluid

Khazardoost S, Yahyazadeh H, Borna S, Sohrabvand F, Yahyazadeh N, Amini E.; Amniotic fluid lamellar body count and its sensitivity and specificity in evaluating of fetal lung maturity. J Obstet Gynaecol. 2005 Apr;25(3):257-9. PMID: 16147729 [PubMed - indexed for MEDLINE]

However L/S ratio and PG estimate are unavailable at several instituitions due to economic and logistics reasons

in this context LBC might be a viable alternative

lamellar bodies can easily be counted using commercial blood cell analysers

therefore LBC is very quick, simple and inexpensive test

Khazardoost S, Yahyazadeh H, Borna S, Sohrabvand F, Yahyazadeh N, Amini E.; Amniotic fluid lamellar body count and its sensitivity and specificity in evaluating of fetal lung maturity. J Obstet Gynaecol. 2005 Apr;25(3):257-9. PMID: 16147729 [PubMed - indexed for MEDLINE]

Several studies have shown lamellar body counts to be

accurate predictors of fetal lung maturity (Greenspoon

et al 1995)

Recently, it was demonstrated that the LBC could

reduce by approximately three-quarters the need for L/S

assays (Lewis et al 1999)

What is a test's sensitivity and specificity?

Sensitivity and specificity are parameters that express something about the tests’ performance;

Sensitivity is the test ability to detect a disease when it is effectively present – true positives. If the babies suffer from respiratory distress syndrome, LBC result should be positive.

Specificity is the test ability to detect true negative. If the babies are healthy, LBC result should be negative.

Search on Wickipedia for sensitivity and specificity.

Why is this meta-analysis important?

Problem: There is some doubt about the sensitivity and specificity of LBC in determination of RDS

So... This meta-analysis allows the analysis of all articles about this topic on Pubmed till October 2005 and it answers the question: “What is the sensitivity and specificity of amniotic fluid lamellar body count in detection of respiratory distress syndrome?”

Study Design

Systematic review with meta-analysis, whenever aggregation of articles by cut-off values was possible.

All studies results and differences on the conclusions were analyzed in order to answer the question:

“What’s the specificity and sensitivity of amniotic fluid

lamellar body count in detection of respiratory distress syndrome?”

Steps of article:

1. Search for literature2. Use predefined Inclusion/Exclusion Criteria to select the article3. Evaluate quality of articles4. Extract data5. Statistical analysis of data

Research methods

• Database: Medline

• Limits: publications until 2005/10; Humans

• The search aimed at finding the most evidence which could be useful in estimating the sensitivity and specificity of lamellar body count from the amniotic fluid in detection of respiratory distress syndrome in Newborn

Search Plan

Objective: find articles related to diagnostic studies referring to the respiratory distress syndrome.

1.Find articles of all diagnostic studies2.Find articles of all diagnostic studies referring to amniotic fluid3.Find articles of all diagnostic studies referring respiratory distress syndrome, Newborn4.Find articles of all diagnostic studies related to lamellar body count5.Gather all data

Search process

Sensitivity and Specificity

Using a recommended search strategy* (sensitiv*[Title/Abstract] OR sensitivity and specificity[MeSH Terms] OR diagnos*[Title/Abstract] OR diagnosis[MeSH:noexp] OR diagnostic * [MeSH:noexp])

MeSH (Medical Headin Subject): sensitivity and specificity[MeSH Terms] ; diagnosis[MeSH:noexp ; diagnostic * [MeSH:noexp]Search 1: N=1962714 articles

Haynes RB, Wilczynski NC for the Hedges Team. Optimal search strategies for retrieving scientifically strong studies of diagnosis from MEDLINE: analytical survey. BMJ. 2004 May 1;328(7447):1040

We attempted to find most studies containing the following criteria:

1. diagnosis studies related to amniotic fluid2. all diagnosis studies related to respiratory distress syndrome in

newborn (RDS) a.k.a. “(hyaline membrane disease”), directly related to lung maturity (which is behind the RDS and can be, in some cases by amniocentesis).

3. obtain diagnosis studies related to the given intervention, lamellar body count,

Query: (sensitiv*[Title/Abstract] OR sensitivity and specificity[MeSH Terms] OR diagnos*[Title/Abstract] OR diagnosis[MeSH:noexp] OR diagnostic * [MeSH:noexp] OR diagnosis,differential[MeSH:noexp] OR diagnosis[Subheading:noexp]) AND ("amniotic fluid" [MeSH]) AND ("respiratory distress syndrome, Newborn" [MeSH] OR "lung maturity" OR "respiratory distress syndrome" OR "FLM" OR “surfactant” OR “hyaline membrane”) AND ("lamellar body count" OR "lamellar bodies" )

N=25 articles

Due to the restrict number of articles found required another search on SCOPUS, using the query: “Lamellar body count” AND “Respiratory distress syndrome”

No other articles were found that were not included in the medline search.

Critics on research methods

The research was based only on two databases, apart from other data source such as Cochrane central or manual research and final Medline research query may have been too specific[2].

Pai M, McCullock M, Gorman JD, Pai N, Enanoria W, Kennedy G, Tharyan P, Colford JM Jr. Systematic reviews and meta-analyses: Na illustrated, step-by-step guide. The National Medical Journal of India 2004; 17(2): 86-95

•3 independent reviewers read the titles and

abstract selecting them according to the

inclusion/exclusion criteria.

Title and abstract review

Inclusion criteria

Studies’ inclusion was processed by the selection of articles that evaluated sensitivity and specificity of diagnostic method of amniotic fluid lamellar body count, in the detection of Respiratory Distress Syndrome.

The articles included were written in the following languages known by the revisers: English, French, Spanish and Portuguese. With the application of previously defined inclusion criteria, 14 articles were considered valid.

Exclusion criteria

In a second stage of analysis, articles were excluded according to the following criteria:

compare different techniques not referring to lamellar body count tests;

include the results of lamellar body count along with the results of other tests, becoming impossible to calculate the sensitivity and specificity of the test;

omit the results namely the sensitivity and specificity of lamellar body count.

Quality analysis of the studies In a third stage the selected articles were analysed by two independent revisers in order to evaluate their quality using STARD checklist [3], used for evaluation of diagnostic studies.

To every affirmative topic was given 1 point and to negative ones zero points.

The evaluation of quality was based on the sum of points resultant from article analysis, within a maximum of 25 points per article.

All of the 6 selected studies held the fundamental requirements to proceed to its inclusion in a meta-analysis.

Articles quality was compared using the mean of the two revisers results.

[3] Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. The Standards for Reporting of Diagnostic Accuracy Group.Croat Med J. 2003 Oct;44(5):635-8.

Characteristics of participants

According to the article aim, the units of analysis were all the

diagnosis studies included based on the methods previously

defined.

Data extraction

True Positives, True Negatives; False positives; False negatives

Article ID

Values of:

Sensitivity

Specificity

Cut-off points

Outcome Variable

Confidence Interval (95%)

Software used for input and analysis: Metadisc 1.2

Statistical analysis

The agreement in title, abstract and full text review -> Kappa Cohen testAgreement in quality measure -> ICCSoftware used: SPSS 13.0

*Devillé, Walter et all - Conducting systematic reviews of diagnostic studies - Didactic guidelines; BMC Medical Research Methodology 2002, 2:9

Data analysis*: • Presentation of the results of individual studies• Searching for the presence of heterogeneity• Testing of the presence of an (implicit) cut-point effect• Dealing with heterogeneity• Deciding which model should be used if statistical pooling is

appropriate• Statistical pooling Software used: MetaDiSc 1.2

Results

From the 13 articles selected from title and abstract review

9 full-text were obtained

6 articles were included in the metanalysis

Agreement

The agreement evaluation test for the title, abstract and full-text review was performed using Cohen Kappa agreement test-1960 to study this property between the choices of different revisers.

Cohen-Kappa in title and abstract evaluation: 0.818

Full-text evaluation: 1.000

Based on the conclusions of Landis and Koch(1977), we may classify these agreements as good.

Quality evaluationICC=0.72Mean quality: 16.25Lower value:15Highest value:22

Sensitivity table

Author year cutoff Sen [95% Conf. Iterval.]

TP/(TP+FN) TN/(TN+FP) Quality (mean)

Khazardoost

2005 50000 0,850 0,621 - 0,968

17/20 42/60 17.5

Beinlich 1999 30000 0,821 0.631-0.939 23/28 62/62 15

Ghidini 2005 37000 0,941 0.713-0.999 16/17 54/85 15

DeRoche 2002 37000 0,821 0.631-0.939 23/28 62/62 15

Dalence 1995 30000 1.000 0.794-1.000 16/16 73/114 22

Dalence 1995 10000 0.750 0.476-0.927 12/16 108/114 22

Ross 2002 41500 0.905 0.774-0.973 38/42 78/89 19.5

Ross 2002 32000 0.905 0.774-0.973 38/42 76/89 19.5

Ross 2002 24000 0.786 0.632-0.897 33/42 89/89 19.5

Ross 2002 21000 0.714 0.554-0.843 30/42 89/89 19.5

Sensitivity graphic

Homogeneous sensitivity independent from cut-off value.

Specificity table

Author year cutoff Spef [95% Conf. Iterval.]

TP/(TP+FN) TN/(TN+FP) Quality

khazardoost 2005 50000 0,700 0,568 - 0,812

17/20 42/60 17.5

Beinlich 1999 30000 1,000 0,942 - 1,000

23/28 62/62 15

Ghidini 2005 37000 0,635 0,524 - 0,737

16/17 54/85 15

DeRoche 2002 37000 1,000 0,942 - 1,000

23/28 62/62 15

Dalence 1995 30000 0,640 0,545 - 0,728

16/16 73/114 22

Dalence 1995 10000 0,947 0,889 - 0,980

12/16 108/114 22

Ross 2002 41500 0,876 0,790 - 0,937

38/42 78/89 19.5

Ross 2002 32000 0,854 0,763 - 0,920

38/42 76/89 19.5

Ross 2002 24000 1,000 0,959 - 1,000

33/42 89/89 19.5

Ross 2002 21000 1,000 0,959 - 1,000

30/42 89/89 19.5

Specificity graphic

Many factors affect specificity:*

•Blood presence;

•Vaginal mucus;

•Transient trachypnea

*Neerhof MG, Dohnal JC, Ashwood ER, Lee IS, Anceschi MM. Lamellar body counts: a consensus on protocol.

Obstet Gynecol. 2001 Feb; 97(2):318-20.

There are groups with similar specificity->Subgroup analysis

Cut-off point=30000

Heterogeneity present Why? Difference on qualityDalence et al : 22Beilinch et al : 15

Sensitivity graphic

Specificity graphic

Cut-off point=37000

Heterogeneity present in specificity and homogeneity in sensitivity

Cut-off 30000-50000 and similar countersVery homogeneousWhy? Maybe similar counters

Counter used in Dalence: Coulter STKR/ Coulter S + IV (both were calibrated)/ Sysmex 780 (not user modifiable)Counter used in khazardoost: Coulter STKRCounter used in ghidini: Coulter STKR

ConclusionDiferences in the experimental protocol lead to different results *

Lack of simillar cut-offs make statistical analysis difficult *

Materials used affect results+

For any cutoff, the sensibility is high ->Great screening test

*Neerhof MG, Dohnal JC, Ashwood ER, Lee IS, Anceschi MM. Lamellar body counts: a consensus on protocol.

Obstet Gynecol. 2001 Feb; 97(2):318-20.

+Bowie LJ, Shammo J. Lamellar body number density and the prediction of respiratorydistress syndrome. Am J Clin Pathol 1991; 95:781-6