2. EL SISTEMA AUSTRALIANO DE CONTABILIDAD DEL AGUA
2.2. DEFINICIONES
2.2.5. Propuestas de mejora de la metodología de contabilidad
3.4.1 Methods
The same methods were used as specified in section 2.4.1.
3.4.2 Results of the economic literature review
A total of 153 papers were identified in the literature search. All were excluded based on title
and abstract. No economic studies were included for this review question.
3.4.3 Economic modelling
The evidence gathered for this review question was included in the economic modelling
conducted for the case-finding review question. Please see section 2.4.3 and appendix O.
3.5 Evidence statements
3.5.1 Clinical evidence statements
Sensitivity and specificity
Evidence for the accuracy of 2 different diagnostic scoring systems (compared with the gold
standard of genetic testing for mutations in LDLR, APOB and PCSK9 genes) was evaluated
for different diagnostic thresholds.
Simon Broome criteria
Very low quality evidence from 4 studies with 1,872 people suggested the Simon Broome
definite criteria had low sensitivity (0.36 [0.186, 0.581]) and high specificity (0.86 [0.158,
0.995]). Sensitivity analysis (3 studies, 666 people, very low quality evidence) removing the
Haralambos (2015) study also showed low sensitivity 0.335 [0.156, 0.578] and high
specificity (0.804 [0.073, 0.950]).
Very low quality evidence from 4 studies with 1,872 people suggested the Simon Broome
possible and definite criteria had high sensitivity (0.89 [0.845, 0.924] and low specificity
(0.287 [0.160, 0.459]). Sensitivity analysis (3 studies, 656 people, very low quality evidence)
removing the Haralambos (2015) study also showed high sensitivity 0.87 [0.825, 0.905] and
low specificity (0.325 [0.173, 0.526]).
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DLCN criteria
Low quality evidence from 4 studies with 1,088 people suggests that DLCN definite criteria
(>8) had a moderate sensitivity of 0.567 [0.460, 0.669] and high specificity of (0.802 [0.713,
0.869]).
Low quality evidence from 4 studies with 1,531 people suggested that DLCN probable and
definite criteria (>5) had high sensitivity (0.868 [0.711, 0.946]) but had low specificity (0.457
[0.320, 0.601]). Sensitivity analysis (3 studies, 859 people, moderate quality evidence)
removing the Haralambos (2015) study showed a high sensitivity of 0.807 [0.716, 0.874] and
moderate specificity (0.517 [0.472, 0.561]).
Low quality evidence from 4 studies with 936 people suggested that DLCN possible,
probable and definite criteria (>2) had high sensitivity 0.967 [0.939, 0.983] respectively). The
specificity was low (0.125 [0.057, 0.253]).
3.5.2 Health economic evidence statements
No economic evidence was identified in the literature for this review question. The DLCN
criteria is slightly more expensive to administer than the Simon Broome criteria due to the
additional clinical time required to obtain extra information. However, because the DLCN
criteria has a higher specificity compared with the Simon Broome criteria, it is likely to result
in a reduced use of lipid clinic resources, including genetic testing, through the increased
confidence that people who are referred are more likely to have FH.
3.6 Evidence to recommendations
Committee discussions Relative value of
different outcomes The committee discussed that sensitivity and specificity were the most important outcomes, and that there needed to be a compromise between high sensitivity (true positive rate) and high specificity (true negative rate). Whilst FH can be treated relatively easily, the committee noted that the test needed to be adequately specific to avoid unnecessary referrals for genetic testing. The committee further discussed that the specificity required depended on whether a one or two stage process was to be used: a two stage process (using a scoring system to decide whether to refer to secondary care for further assessment) would tolerate a lower specificity (higher false positive rate) in the first stage of the process.
Quality of evidence Very low quality evidence was available for the sensitivity and specificity of the Simon Broome definite criteria and Simon Broome definite + probable criteria to identify people with a genetic mutation. Low quality evidence was available for sensitivity and specificity for the Dutch Lipid Clinic Network (DLCN) criteria (possible, probable, definite, (score >2); DLCN probable and definite criteria, (score >5) and DLCN definite criteria (score >8) to identify people with a genetic mutation.
A sensitivity analysis was undertaken for the Simon Broome possible + definite and definite criteria to see whether the removal of the Haralambos (2015) data had any effect. A sensitivity analysis was undertaken for the outcomes of DLCN >5, Simon Broome possible and definite and Simon Broome definite; removing data from the Haralambos (2015) study due to reporting of imputed values for the Simon Broome diagnostic accuracy and because this study used a modified DLCN criteria.
There was no significant difference when Haralambos (2015) was removed from the meta-analysis for Simon Broome possible + definite and definite criteria. A sensitivity analysis was also undertaken on DLCN score >5 (probable and definite) as Haralambos (2015) used a modified DLCN criteria, which reduces the score depending on triglyceride concentration. None of the sensitivity analyses made a significant difference to the results.
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Committee discussions
No evidence was reported for PPV and NPV because the heterogeneity in prevalence rates between-studies was considered to be too large for pooled results to be robust.
Results for the outcome of diagnostic yield were reported in section 2: case finding and are not reported here to avoid duplication.
Trade-off between
benefits and harms The committee noted that there is a trade-off between the sensitivity and specificity of diagnostic criteria: the benefit of diagnosis and treatment of FH vs unnecessary referrals of people who turn out not to have FH.
The committee discussed that Simon Broome definite criteria had the lowest sensitivity and highest specificity for predicting a positive genetic diagnosis. Consideration was given to the high sensitivity and low specificity of Simon Broome possible + definite criteria: it was discussed that there was very serious inconsistency between studies. The committee went on to assess the evidence for DLCN criteria to predict a genetic FH mutation: The topic experts discussed that the DLCN criteria score of >2 (possible,
probable and definite) had excellent sensitivity, but the low specificity could lead to many people who did not need referrals to secondary care receiving them. It was noted that a DLCN score of >5 (probable or definite) gave a high enough sensitivity, however specificity was poor (<50%). Conversely, a DLCN score of >8 (definite) had high specificity but moderate sensitivity, which could lead to a substantial number of people with FH being missed (increased false negatives). The committee concluded that using either a DLCN score of >5 or Simon Broome possible and definite criteria to refer on to genetic testing gave the best compromise between adequate sensitivity and specificity. The Committee agreed that the evidence was not sufficiently robust to be able to determine which of these two alternatives was most appropriate, and therefore agreed it was correct to recommend that either could be used.
The committee considered the recommendations in the diagnosis section in terms of this evidence review and decided that recommendations 1.1.4, 1.1.7 to 1.1.12, 1.1.14 and 1.1.16 should stand unchanged.
Trade-off between net health benefits and resource use
This review question was used to inform the economic modelling conducted for case finding.
No economic studies were identified in the systematic review. The committee discussed that the DLCN criteria is slightly more expensive to administer than the Simon Broome criteria due to the additional clinical time required to obtain extra information. However, because the DLCN criteria has a higher specificity compared with the Simon Broome criteria, it is likely to result in a more appropriate use of lipid clinic resources, including genetic tests, through the increased confidence that people who are referred are more likely to have FH.
Other
considerations
Given that both Simon Broome possible and definite and DLCN criteria >5 are similar with regards to sensitivity and specificity of diagnosing FH, the committee asked the Topic Experts about the feasibility of using either Simon Broome or DLCN criteria in primary care. It was noted that the DLCN criteria could be viewed as being more complex than Simon Broome criteria. The committee discussed that it is currently easier to search
primary care records using Simon Broome criteria, due to coding of records. However, in practice, electronic records would only be searched for total cholesterol and/ or LDL-C measurement and the rest of the assessment using either the Simon Broome or DLCN criteria would be undertaken by a healthcare professional. The committee went on to discuss that there may be the need for education amongst health professionals with regards to using DLCN criteria for diagnosing FH in primary care. This is because the DLCN criteria may be less familiar than Simon Broome criteria; however this was not considered an issue because clinicians would now have the option of using either Simon Broome or DLCN criteria to clinically diagnose FH. Furthermore, there is significant overlap in the criteria used by both
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Committee discussions
Simon Broome and DLCN: both criteria assess LDL-C concentration, presence of DNA mutation, personal and family history and clinical features. It was considered that clinicians who currently assess patients for FH are already familiar with these aspects of FH, and that introducing the option to use DLCN to assess whether a person may have FH was merely a case of becoming more familiar with the DLCN scoring system rather than learning new clinical features or procedures.
The committee considered the assessment of children at risk of FH because of one affected parent. It was stated that it is not appropriate to use DLCN or Simon Broome criteria to assess people in this patient group. Children at risk of FH because of an affected parent had previously been assessed using either LDL-C concentration of DNA testing; however the committee discussed this was no longer appropriate and children of people diagnosed with FH should have a DNA test only.
The committee discussed the clinical need for further research in this clinical area and added a research recommendation comparing the use of the Simon Broome and DLCN criteria in identifying FH in a general population.
3.7 Recommendations
6. Use the Simon Broome or Dutch Lipid Clinic Network (DLCN) criteria to make a
clinical diagnosis of FH in primary care settings. This should be done by a
healthcare professional competent in using the criteria. [2017]
7. Refer the person to an FH specialist service for DNA testing if they meet the
Simon Broome criteria for possible or definite FH, or they have a DLCN score
greater than 5. [2017]
8. Inform all people who have an identified mutation diagnostic of FH that they have
an unequivocal diagnosis of FH even if their LDL-C concentration does not meet
the diagnostic criteria (see recommendation 6). [2008, amended 2017]
3.8 Research recommendations
3.8.1 Compare the Simon Broome criteria and the DLCN score in a prospective
cohort of general population subjects.
What is the clinical and cost-effectiveness of identifying people with FH by using the DLCN
score compared to Simon Broome criteria in the general population?
Why this is important
There is a lack of good quality evidence on direct comparison of Simon Broome and DLCN
score in diagnosing clinical FH when compared to the gold standard of next generation
sequencing for the three common FH-causing genes.
Table 15: Specification for research recommendation
PICO Population:
General population
Index test:
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DLCN score
Reference test:
Next generation sequencing of APOB, PCSK9 and LDLR.
Outcomes:
Sensitivity of mutation detection Specificity of mutation detection
Outcomes should be subgrouped by age, gender, age of MI and smoking status.
Current evidence base Currently, there is no evidence for a direct comparison of Simon Broome
and DLCN compared to a reference standard of NGS for all 3 FH causing mutations.