National Health Committee
Tier 3: Alternative
investigation and
management of haematuria in
primary care using Cxbladder
Triage to rule out urothelial
cancer
National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
National Health Committee (NHC)
The National Health Committee (NHC) is an independent statutory body charged with prioritising new
and existing health technologies and making recommendations to the Minister of Health.
It was reformed in 2011 to establish evaluation systems that would provide the New Zealand people
and the health sector with greater value for money invested in health.
The NHC Executive is the secretariat that supports the Committee. The NHC Executive’s primary
objective is to provide the Committee with sufficient information for it to make decisions regarding
prioritisation and reprioritisation of interventions and services. They do this through a range of
evidence-based products chosen according to the nature of the decision required and timeframe within
which decisions need to be made.
The New Zealand Government has asked that all new diagnostic and treatment (non-pharmaceutical)
services, and significant expansions of existing services, are to be referred to the NHC.
In August 2011 the NHC was appointed with new Terms of Reference and a mandate to establish the
capacity to assess new and existing health technologies. Its objectives (under Section 4.2 of its Terms
of Reference – www.nhc.health.govt.nz) include contributing to improved value for money and fiscal
sustainability in the health and disability sector by:
 providing timely advice and recommendations about relative cost-effectiveness based on the best
available evidence;
 providing advice and recommendations which influence the behaviour of decision makers including
clinicians and other health professionals;
 providing advice and recommendations which are reflected in resource allocation at national,
regional and local levels; and
 contributing to tangible reductions in the use of ineffective interventions and improved targeting to
those most likely to benefit.
In order to achieve its objectives under Section 4.2 and to achieve ‘Value for Money’, the NHC has
adopted a framework of four assessment domains – Clinical Safety & Effectiveness; Economic; Societal
& Ethical; and Feasibility of Adoption – in order that assessments cover the range of potential
considerations and that the recommendations made are reasonable.
It is intended that the research questions asked will fall across these domains to ensure that when the
Committee comes to apply its decision-making criteria, it has a balanced range of information available
to it. When the NHC is setting those questions they will have the decision-making criteria in mind.
The 11 decision-making criteria will assist in the determination of the NHC work programme and in the
appraisal and prioritisation of assessments.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
Contents
Executive Summary............................................................................................ 5
1. Context ........................................................................................................ 7
2.1 Urinary biomarkers testing .................................................................................................. 9
2.2 Target group for urinary biomarker testing ......................................................................... 9
2.3 Cxbladder tests .................................................................................................................. 10
Assessment ...................................................................................................... 10
3. Target Population ...................................................................................... 11
3.1 Bladder cancer epidemiology and burden of disease........................................................ 11
3.2 Burden of Disease .............................................................................................................. 12
4. Clinical safety and effectiveness ................................................................ 14
4.1 Methods ............................................................................................................................. 14
4.2 Measurement of test and diagnostics performance ......................................................... 15
4.3 Risk stratification from features of clinical presentation .................................................. 16
4.4 Cxbladder Detect ............................................................................................................... 17
4.5 Cxbladder Triage ................................................................................................................ 17
4.6 Clinical expectation for the operation of Cxbladder Triage ............................................... 18
5. Economic considerations ........................................................................... 19
5.1 Methods ............................................................................................................................. 19
5.2 Use of diagnostic resources ............................................................................................... 19
5.3 Estimated resource use for current diagnostic model of target population 22
5.4 Utilisation of Cxbladder Triage........................................................................................... 25
5.5 Factors to consider regarding the implementation of Cxbladder Triage into routine
clinical practice ........................................................................................................................ 26
5.6 Potential Benefits of Cxbladder Triage .............................................................................. 27
6. Societal and ethical considerations ............................................................ 30
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
6.1 Methods ............................................................................................................................. 30
6.2 Higher order considerations .............................................................................................. 31
6.3 What is known - False test results ..................................................................................... 32
6.4 Equity and acceptability ..................................................................................................... 34
7. Feasibility of adoption ............................................................................... 34
7.1 Methods ............................................................................................................................. 34
7.2 Workforce .......................................................................................................................... 34
7.3 Infrastructure ..................................................................................................................... 35
7.4 Policy congruence .............................................................................................................. 35
7.5 Patient factors .................................................................................................................... 35
8. Opportunity for Learning ........................................................................... 36
8.1 Development of the evidence base ................................................................................... 36
8.2 Development of experience with algorithm based diagnostics ........................................ 38
8.3Development of higher order experience .......................................................................... 38
References ....................................................................................................... 39
National Health Committee (NHC) and Executive ............................................ 41
Disclaimer ........................................................................................................ 41
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
Executive Summary
Cxbladder Triage has the potential to change the model of care for the diagnosis of urothelial cancer
by enhancing diagnostic options and acceptability in patients presenting with haematuria by
accurately identifying those patients that do not have urothelial carcinoma. This change in clinical
utility is driven by enabling physicians in the primary care setting to use novel molecular diagnostic
products. The use of Cxbladder Triage in primary care offers the potential to enhance continuity of
care for patients, deliver more care locally, reduce demand for specialist urology services and lower
overall costs to the healthcare system.
Cxbladder Triage has been developed by Pacific Edge (PE). It is expected to be used as part of the
assessment of patients presenting with microscopic haematuria in primary care. This novel test
combines the use of clinical and genomic bio-markers in an algorithm that may enable primary care
clinicians to ‘triage out’ those patients who have a low probability of having urothelial carcinoma.
This option has not been possible before.
The performance of the genomic component is known through the development of the PE diagnostic
product Cxbladder Detect. The estimation of the performance of the combined genomic and
phenotypic components, Cxbladder Triage, has been developed on patients referred to secondary
care with macroscopic haematuria and shows enhanced detection of urothelial cancer compared to
Cxbladder Detect. Validation was carried out on a small population of patients in the secondary care
setting who had confirmed microscopic haematuria. Assessment of the performance of Cxbladder
Triage in an appropriate primary care patient population is necessary to further validate Cxbladder
Triage’s performance.
There is a lack of data on how patients suspected of having bladder cancer are currently investigated
in primary care and whether there is variability across practitioners in how this is done. There is also
a lack of data about investigation of patients suspected of having bladder cancer in secondary care.
Better understanding of this aspect of clinical care would inform the resources currently devoted to
investigation of patients presenting with haematuria potentially as a result of underlying urothelial
carcinoma. Significant benefits may achieved if there are technologies that can be applied in the
primary care setting that will identify patients with a low risk of urothelial carcinoma and hence may
not require a full urological work-up for urothelial carcinoma in a secondary care setting.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
The number of people presenting to primary care with any haematuria in New Zealand may lie
between 17,000 and 48,000 with between 1,600 and 3,600 with microscopic haematuria being
assessed in secondary care. Based on the information currently available, it is estimated that the
addition of Cxbladder Triage to the diagnostic model of care for urothelial cancer has the potential
to significantly enhance clinical care in primary care with improved continuity of care and more
convenient care delivery for patients. The data published to date on Cxbladder Triage indicates that
approximately 40% of patients could avoid the referral to secondary care for further costly and
relatively invasive investigations. A reduction in referrals will potentially release urological specialist
and diagnostic imaging resources and allow more timely access to services for those who still require
referral. Between $0.8 and $1.8 million of health care costs may be avoided.
An Innovation Evaluation of Cxbladder Triage on a nationally representative sample of patients
would allow validation of its performance and assess barriers to its uptake and assessment of quality
control measures of sample collection and transportation. The evaluation would also inform the
current standard model of care and thereby the impact on resource use.
An Innovation Evaluation and engagement with the technology developer will help the National
Health Committee to develop its understanding of how to fulfil its strategic aim to pull ‘fit for
purpose” technology into the New Zealand health sector.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
1. Context
The National Health Committee (NHC) is interested in building the capability to pull ‘fit for purpose’
technology into the New Zealand health sector in an effective and expedient manner for the benefit
of patients, populations and the New Zealand health care sector. To this end the NHC has been
working with Pacific Edge a New Zealand technology developer and cancer diagnostic service
provider, to understand how it can work with industry and to understand the issues and challenges
in brokering this new approach. In particular the NHC is trying to understand some higher order
issues including:

How is this new technology different from existing interventions and therefore how does it
add value or change the overall utility of the model of care?

How will it be applied and what impact will it have on the system?

How broad and significant are the impacts – do they move beyond a component of a model
of care to change the way the system and society operate?

How do you practically and expediently pull technologies into use?

Are our current business systems and processes fit for purpose to achieve this, if not what
changes are required for New Zealand to continue to be a leader in this field?

If the technology is significantly different then how will the NHC’s assessment and validation
processes have to change to ensure appropriate assessment and how quickly can we make
these changes?
The NHC has identified that working collaboratively with a technology developer to test a potential
new intervention in a controlled environment will allow for two outcomes. Firstly to explore a
potential new medical technology with existing peer reviewed scientific and clinical performance,
that if adopted, would be expected to change the detection, evaluation and management model of
care for urothelial carcinoma. Secondly to provide the Committee with an opportunity to test out
the issues identified above and make definitive recommendations for a more effective approach to
other potential technologies, devices and products that show enhanced clinical utility.
Pacific Edge has developed a suite of laboratory tests using mRNA1 biomarkers present in urine that
assist in the clinical diagnosis and management of urothelial cancer. These tests are typically used in
secondary care, by urology specialists, to assist with evaluation of undifferentiated referrals from
primary care and to manage the prevalent population of patients with known urothelial cancer.
1
messenger Ribonucleic acid
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
The triage of patients with symptoms indicative of urothelial cancer undertaken with certainty in
primary care has the potential to create a step change in the diagnostic model of care for this type of
cancer.
Pacific Edge has developed a new composite biomarker diagnostic tool Cxbladder Triage which
combines the urinary biomarkers used in their secondary care laboratory test Cxbladder Detect with
patient clinical (phenotypic) information to provide primary care clinicians with a diagnostic tool that
allows for better risk stratification to aid in the preliminary evaluation of haematuria and referral to
secondary care.
In order for the NHC to understand the potential role and utility of this new diagnostic tool both
clinically and in applying its ‘pull and embed’ strategy, it has earlier completed a Tier 2 assessment
which set out the model of care for haematuria in the primary care setting and discussed the role of
biomarker tests in diagnosis. Briefly, both cytology and cystoscopy have limitations in the detection
of bladder cancer. Cytology requires specialist expertise, and has a relatively low sensitivity.
Cytoscopy cannot detect upper urinary tract cancers, and is an invasive process. Biomarker tests are
urinalysis tests and thereby non-invasive. They test for genetic (DNA2, RNA or protein) markers of
urothelial carcinoma.
At their November 2014 meeting the NHC requested that the Executive perform a Tier 3 assessment
of the potential role of urinary biomarkers in the detection and management of haematuria and
urothelial cancer. A Tier 3 assessment of the clinical safety and effectiveness of urinary biomarkers
particularly Cxbladder Detect in comparison with others in the market was provided to the
Committee in December 2014. The Committee then requested that Pacific Edge’s new product that
is a composite of genotypic and phenotypic biomarkers for the early triaging-out of patients with a
low risk of having urothelial carcinoma (Cxbladder Triage) be assessed.
Cxbladder Triage is a multi-biomarker test developed by Pacific Edge in New Zealand on a group of
patients collected from eleven sites in both New Zealand and Australia. It combines clinical data as
four phenotypic biomarkers and data from the quantitative measurement of the expression of five
genomic biomarkers in a small volume of urine using a quantitative polymerase chain reaction (RTqPCR). Four of the genomic biomarkers are associated with urothelial cancer and one is a genomic
biomarker of an inflammatory process.(1)
2
Deoxyribonucleic acid
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
The purpose of this NHC assessment was to primarily explore the implications of both the change in
the current clinical model for the management of the large number of patients presenting in primary
care with non-specific haematuria potentially caused by urothelial carcinoma and to identify higher
order ‘pull and embed’ strategy issues that would need to be explored at the next stage of the
relationship with Pacific Edge.
This paper draws on and does not repeat the the risk factors for bladder cancer, the histological
types, clinical presentation, diagnostic methods and clinical outcomes for haematuria as discussed in
Tier 3 assessment: The effectiveness of urinary biomarker genotypes (Cxbladder Detect) in the
investigation of Haematuria in Primary Care.
2. Background
Current options for diagnosis of urothelial cancer include cytology, which does not perform well in
detecting malignancy. It has a sensitivity of 40%–60%, with significant inter-observer variability and
needs interpretation by specialists.(2) The standard diagnostic option, cystoscopy, is invasive(3) and
cannot alone detect upper tract urothelial cancers, so imaging is also needed. Previous analysis of
the effectiveness of urinary biomarker genotypes (Cxbladder Detect) in the investigation of
haematuria in primary care has shown the relatively superior performance of Cxbladder Detect
compared to alternative urinary biomarker tests. Pacific Edge has further developed their technology
and has released a second product Cxbladder Triage for triaging-out patients with a low probability
of having urothelial carcinoma. Cxbladder Triage has improved performance over Cxbladder Detect
in ruling out the presence of the disease and is intended to be applied in the preliminary evaluation
of haematuria such as in the primary care setting.
2.1 Urinary biomarkers testing
Testing for urinary biomarkers offers an alternative tool in the diagnosis of haematuria. Diagnostic
urinary biomarkers are non-invasive and could potentially overcome the limitations of current
diagnostic options. If effective in the primary care setting, they could identify patients without
urothelial cancer who present with haematuria, and avoid specialist referral and further
investigation.
2.2 Target group for urinary biomarker testing
Clinical assessment of urinary tract cancer risk is performed by assessing the presenting clinical
features, whether the blood in the urine is visible or invisible, other symptoms, and presence of risk
factors and identification of alternative clinical explanations for haematuria. Clinical uncertainty
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
about the underlying condition together with risk factors for malignancy drives the need for further
investigation.
The potential target group for genetic based marker testing are patients who present in primary care
with either macroscopic (visible) or microscopic (invisible) haematuria, and who have a high risk of
an underlying bladder cancer. These are patients that have undergone preliminary clinical
assessment to exclude other clinical explanations, such as infection or intrinsic renal disease,
including renal carcinoma, who have macroscopic or persistent microscopic haematuria that is
unexplained and for whom there is ongoing clinical concern of underlying urothelial cancer.
Analysis in this document will consider the application of Cxbladder Triage to those patients
considered lower risk for bladder cancer on the basis of age or gender, and including patients
diagnosed with persistent microscopic haematuria within the primary care setting. This group is
considered the proposed target population for Cxbladder Triage by Pacific Edge.
2.3 Cxbladder tests
Cxbladder Detect is a multi-plex mRNA test developed by Pacific Edge in New Zealand. It uses RTqPCR amplification to quantify five mRNA markers of genes associated with urothelial cancer.(1)
Cxbladder Triage is a composite biomarker segregation index that combines the genomic data with
clinical data to improve test performance.(4)
Assessment
This assessment analyses whether using Cxbladder Triage, a urinary composite biomarker test
applied in the preliminary evaluation of haematuria within the primary care setting, would be
clinically effective in the diagnostic model of care for urothelial cancer and considers how it could
impact clinical utilisation and costs.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
3. Target Population
3.1 Bladder cancer epidemiology and burden of disease
The following epidemiological and burden of disease data are presented for bladder cancer in its
totality. The focus of this report however is the possible intervention for low risk haematuria
patients including those identified with microscopic haematuria rather than all patients with
haematuria. The data for incidence, mortality and burden of disease are not reported with specific
reference to the mode of presentation and so assumptions have been made to attribute these
measures to the microscopic haematuria population.
Estimation can be made for the contribution of presentations with microscopic haematuria versus
macroscopic haematuria to the total population of patients with bladder cancer. The incidence rate
of bladder cancer is about four to five times higher in those patients presenting with macroscopic
haematuria compared to those with microscopic haematuria in secondary care and with about
approximately equal clinical presentation. (5-7) Patients who present with microscopic haematuria do
not differ in stage of urothelial cancer disease at diagnosis with those who present with macroscopic
haematuria.(4) So it can be estimated that the presentation with microscopic haematuria accounts
for around 17% to 20% of the disease burden, incidence and mortality.
In New Zealand in 2011, bladder cancer was the 13th most common cancer registration and cause of
death from cancer. Men have higher rates than women of bladder cancer for both registrations and
deaths: in 2011, registration and mortality rates for males were about three times those of females.
There are no clear differences in incidence or mortality between Māori and non-Māori. Registration
rates for bladder cancer were relatively stable between 2005 and 2011, as were mortality rates
between 2000 and 2011. In 2011 there were 324 new cases of bladder cancer; and 126 male and 74
female bladder cancer deaths.(8)
The age-standardised registration rate for bladder cancer shows a step-change reduction by about a
half from 2005 onwards, having been relatively stable over the preceding years. A change in coding
occurred at this point when superficial transitional cell carcinomas were no longer considered
malignant.3
Between 1995 and 2010, there were 7,802 registrations for bladder cancer in New Zealand. Most
registrations were for transitional cell carcinoma (TCC) or ‘Neoplasm, malignant’, while 5.9% (464)
3
Cancer :Historical summary 1948-2010. http://www.health.govt.nz/publication/cancer-historical-summary-1948-2010
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
were of other histological types of bladder cancer including squamous carcinoma, adenocarcinoma
and neuroendocrine carcinoma.
3.2 Burden of Disease
Burden of a Disease is a specific measure of health loss that combines the impact of disease in terms
of deaths and people living with disability. Health loss is estimated using YLLs (years of life lost), YLDs
(years lost through disability) and DALYs (disability-
DALY ‒ Disability-Adjusted Life Year
adjusted life years). One YLL can be thought of as a lost
YLL ‒ Year of Life Lost due to early
death: the number of deaths from the
disease multiplied by the normal life
expectancy at the age at which death
occurs
year of life, while one DALY is a lost year of healthy life.
DALYs combine information on both fatal (early death)
and non-fatal (illness or disability) outcomes, allowing the
YLD
effects of different diseases and injuries to be compared
across population groups and over time.(9)
As Table 1 shows, health loss from bladder cancer is
‒ Year Lost due to Disability for
people living with the health condition
or its consequences, taking into
account the severity of ill health and
disability
DALYs = YLLs + YLDs
greater in men than women and largely accounted for by
YLLs. The DALYs for bladder cancer is 3,168 that is 1.8% of health loss due to cancers.(9)
Applying the assumptions set out above about 20% of the bladder cancer DALYs are attributable to
microscopic haematuria, so about 635 DALYs.
Table 1: Burden of Disease for bladder cancer by sex, 2006
YLL
Bladder Cancer
YLD
DALY
DALY
Male
Female
Male
Female
Male
Female
Total
2,067
786
240
76
2,307
862
3,168
Source: Health Loss in New Zealand: A report from the New Zealand Burden of Disease,
Injuries and Risk factors Study, 2006-2016. Wellington: Ministry of Health
The target population are those patients presenting in primary care with haematuria who, under
current clinical practice, having been assessed and investigated do not have a specific diagnosis and
would be referred for specialist urological assessment by their General Practitioner (GP) in view of
ongoing clinical uncertainty and concern regarding the presence of an underlying malignancy. Within
the target population those presenting with microscopic haematuria are the subject of this
assessment.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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The size of the target population can be estimated from the number of patients currently
investigated because of macroscopic or microscopic haematuria using cystoscopy. Assuming that all
patients referred to urology service have a cystoscopy, as this clinical investigation is standard as
part of clinical assessment, then this population is equivalent to the number of referrals by primary
care physicians and is assumed to have been assessed clinically as being most at risk.
One approach towards estimating the size of the target population is using Cancer Registry data.
There were on average of 360 annual registrations for bladder cancer between 2007 and 2011 (Table
2). International data (5, 6, 10, 11) indicates that about 10% of individuals investigated for haematuria in
secondary care are diagnosed with bladder cancer. Using this detection rate and the mean number
of new diagnoses of bladder cancer, an average annual count of patients investigated for haematuria
of about 3,600 is derived.
However, as noted above coding changes 2005 meant that superficial transitional cell cancer was no
longer considered malignant bladder cancer and the age-standardised registration rate
approximately halved. If the current cancer registry data underestimates total cases by not including
superficial transitional cell cancer, then the number of new cases could be 720 per year, and so the
number of cystoscopies could be around 7,200.
Not all of these patients would be seen in the public health care system as some would be diagnosed
through the private sector.
Table 2: Count of new registrations of bladder cancer by year
Year
Total Count
2007
369
2008
357
2009
361
2010
389
2011
324
Average per year
360
Source: Cancer: New registrations and deaths 2011. Wellington: Ministry of Health
An alternative approach is to use specific data collected by the Auckland Regional Urology Service in
Counties Manukau which covers the combined population of Auckland and Counties Manukau
District Health Boards. This shows that in a 12-month period, 847 people had diagnostic cystoscopy;
in 75% (635) of these it was for investigation of haematuria. Assuming these data to be nationally
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
representative, extrapolating to the whole of New Zealand suggests that there are around 3,200
cystoscopies a year for investigation of haematuria.4
The figure from the first approach includes patients diagnosed in both public and private health care
systems while the second approach considers the public health system alone. The more recent
cancer registration data provides an estimate (3,600) similar to the estimate obtained using the
Auckland Regional Urology Service activity data (3,200) for the annual number of cystoscopies
performed for the investigation of haematuria. The NHC Executive considers the figure of 3,200 to
be a reasonable estimate for the number of patients having cystoscopy for haematuria in the public
health system. Taking account of the cancer registry coding change provides a possible alternative
estimate for the annual number of cystoscopies of 7,200.
Thus, an estimated 3,200 to 7,200 patients a year are estimated to be assessed as clinically high-risk
and referred to public specialist health service; the estimates provide a minimum number of patients
who may be eligible for a new diagnostic test in primary care. International experience indicates that
about 50% of patients assessed in secondary care urology clinics present with microscopic
haematuria. (5, 6, 10-12)
It has been assumed that the microscopic haematuria population accounts for 50% of the patients
undergoing cystoscopy. So it is estimated that a minimum of 1,600 people with microscopic
haematuria undergo cystoscopy annually and that the number could be feasibly up to 3,600.
4. Clinical safety and effectiveness
4.1 Methods
Research Question
The formal research question for the assessment of safety and effectiveness is:
In people with microscopic haematuria in primary care who would otherwise be referred to
secondary care for specialist assessment, is the use of the urinary biomarker test Cxbladder Triage a
safe, and clinically effective tool to aid in the for diagnosis of urothelial cancer, compared with
current standard investigation
4
Using the New Health Tracker population for those aged 18 or more years of age
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
Literature review
A systematic search for evidence was performed, limited to English language as shown in Table 3.
The goal of the search strategy was to inform the presentation of haematuria, the diagnostic process
and outcomes of haematuria including bladder cancer and the effectiveness of diagnostic options.
Table 3: Evidence Search
Database
Search terms
Medline
systematic reviews: MESH terms [bladder cancer]
[biological markers]
systematic reviews: MESH terms [bladder
cancer/diagnostics] [cystoscopy]
Centre for Reviews and Dissemination
MESH terms [bladder cancer] [biological markers]
MEDLINE, Embase, Scopus, Cochrane
Library
MESH terms [Hematuria] and [Primary Health Care]
or [Family Practice/ or General Practice] or [general
practitioners/ or physicians, family/ or physicians,
primary care]
Studies retrieved following the search strategy and were appraised and data were extracted. Further
articles were identified from references in the appraised articles were retrieved and assessed for
relevance.
4.2 Measurement of test and diagnostics performance
Performance of standard laboratory diagnostic tests is measured by their sensitivity (the ability to
correctly detect the disease) and specificity (the ability to detect only the disease). Sensitivity is
important because it describes the test’s ability to correctly identify patients who do have the
condition being tested for. Most importantly, high sensitivity is valuable in ruling out the disease
when the test result is negative. Conversely, specificity is important because it describes the test’s
ability to correctly identify patients who do not have the condition being tested for, so offers the
most utility in ruling-in based on a positive test result. Positive predictive value (PPV) and negative
predictive value (NPV) of tests are other informative performance measures especially in the clinical
setting. They consider performance from the perspective of the test result. The PPV is the
proportion of positive tests for patients that actually have the disease (i.e. the true positive rate),
whereas the NPV is the proportion of negative test results for patients that are truely negative for
the disease (i.e. the true negative rate). So a diagnostic test with a high NPV can be considered to
offer a high level of confidence in a test result which is negative.
Sensitivity and specificity are considered constant features while PPV and NPV are dependent on the
frequency of the condition in the test population. While the sensitivity and specificity remain
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
constant, as the condition of interest becomes more common in the test population the PPV
increases and where the condition of interest becomes less common the NPV increases.
With diagnostic tests that generate a result with a continuous scale the cut-off points for a positive
or negative result can be adjusted to produce what is considered optimum performance under
particular circumstances. Adjustment involves a trade-off between sensitivity and specificity. As
sensitivity is increased, to ensure the detection of disease cases, specificity is reduced. This is
demonstrated in the reported evaluation of Cxbladder Triage with the variation in sensitivity and
specificity with change in the pre-determined test-negative rate.(4)
4.3 Risk stratification from features of clinical presentation
The quantification of risk of clinical outcomes with clinical features to aid diagnosis has been
analysed for the presentation of haematuria and in other clinical circumstances. For example, the
presence or absence of certain clinical features have been used to estimate the risk of streptococcus
as the cause of sore throat and advise on clinical management strategies(13) and aid the diagnosis of
sinusitis in general practice.(14) Risk assessment using clinical features has been used in the context of
urological malignancy.
A United Kingdom (UK)-based study of secondary care patients produced a clinical prediction model
using age, gender, smoking history, microscopic versus macroscopic haematuria, number or
episodes of haematuria and other symptoms where the overall incidence of urological cancer was
9.9%, of which 78% of cases were bladder cancer. The application of the clinical features allows an
estimation of risk in comparison with the baseline risk of malignancy. For example, a patient who
was male, a former smoker with multiple episodes of macroscopic haematuria and no history of
urinary tract infection had a predicted risk of 69% compared with the baseline of 9.9% for
malignancy. A female patient with the same other risk factors has a predicted risk of 47%.(11)
A United States (US) study aimed to assess the value of adding a NMP22 test result to assessment of
risk factors and cytology testing. In this study, the baseline risk of bladder cancer was 6.0%.
Multivariate analysis found men were at 20% greater risk than women, smokers nearly three times
the risk of non-smokers and people with macroscopic haematuria about five times the risk of those
with microscopic haematuria. The model using clinical features had a predictive accuracy of 74%,
which increased to 82% when the NMP22 test result was added. The study reported a scoring
system for the calculation of predicted risk, and macroscopic haematuria was the strongest
predictive factor. For example, from the baseline risk of 6%, a 70-year-old male smoker with visible
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
haematuria would have a calculated risk of about 25%. This rises to about 45% if he also had a
positive NMP22-test.(15)
In a US study of patients referred to urologists with microscopic haematuria the strongest predictor
of malignancy was having a previous episode of macroscopic haematuria. Other factors used were
age, gender, smoking history and haematuria level. Those classified to the low risk group had a
cancer risk of 0.3% compared to a background risk of 2.5%.(16)
These prediction models offer a quantified assessment of clinically available information to calculate
a risk of malignancy. Estimation of risk based on clinical features may indicate that an individual is at
high risk of underlying malignancy and that an intermediate test before the ‘gold standard’ test may
not add value to the decision process.
4.4 Cxbladder Detect
Cxbladder Detect uses an algorithm to combine the results of five mRNA markers detected using RTqPCR. It is designed to detect urothelial cancer in patients presenting with haematuria.
In patients with macroscopic haematuria, Cxbladder Detect has a sensitivity of 82% (detects 82% of
cases) for urothelial cancer. However it has 100% sensitivity for the more high-risk stages and grade
of the disease, whereas the undetected cases (false negatives) were for the most part lower risk
tumours (low grade, stage Ta).
The performance of Cxbladder Detect for the detection of the non-urothelial histological types of
bladder disease is not known. These histological types account for about 5% of bladder cancer cases
internationally(17) similar to the frequency of 6% estimated for New Zealand.5 However, the
individual markers used in the Cxbladder Detect measure abnormal cell turnover of malignant cells
and so theoretically should be able to detect non-urothelial cancers.6
The performance of Cxbladder Detect has not been examined in conjunction with other biomarker
diagnostics.6
4.5 Cxbladder Triage
The Cxbladder Triage combines the genomic data of testing in conjunction with the phenotypic
(clinical) data of the patient (referred to in the published literature as G+P INDEX). The diagnostic
algorithm uses the same genomic technology as Cxbladder Detect (referred to in the published
5
NHC executive analysis of cancer registry data
6
Personal Communication, Pacific Edge. 2014
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
literature as G INDEX). Data are derived from a secondary care population of macroscopic
haematuria patients who have been assessed and selected for referral. The test algorithm derived
from this population has subsequently been applied to a validation population of a small group of
patients with microscopic haematuria.
A sample of 587 patients aged over 45 years was analysed who presented with macroscopic
haematuria and had complete data and who had had conventional clinical evaluation to determine
true clinical outcomes. Urothelial cancer was diagnosed in 72 patients and 515 were urothelial
cancer negative. The clinical variables analysed were age (<60 years and 60 years or more), gender,
smoking history (never versus current or past) and average daily frequency of haematuria. For the
combination of genotypic and phenotypic data, at a level where the test negative rate is 40%, test
performance was maximised, with test sensitivity of 95% and the NPV in the study population of
98% thereby providing a high level of confidence in a negative test result i.e. ruling out those who do
not have urothelial carcinoma. The composite diagnostic (G+P INDEX) performs better than both the
genomic (G-INDEX) and the phenotypic algorithm (P-INDEX) alone. The aim of the composite
diagnostic is to confidently rule out those who do not have urothelial cancer. (4)
Applying these performance parameters to the target population where the proportion of patients
with urothelial cancer is estimated at 4%,(5, 6, 12) the NPV would be 99%.
Table 4 shows the available performance of the Cxbladder biomarkers by sensitivity and specificity.
Table 4: Performance of Cxbladder urinary biomarker tests for diagnosis of urothelial cancer
Tests
Summary Sensitivity (%)
Summary Specificity (%)
Cxbladder Triage (4)
95
45
Cxbladder Detect (1)
82
85
4.6 Clinical expectation for the operation of Cxbladder Triage
The target population of patients with microscopic haematuria is at a relatively low risk of having
urothelial cancer, about 4%, as noted above. However, the current model of care for diagnosis
involves referral to secondary care and investigation with cystoscopy for all patients identified by the
current diagnostic pathway. As such, clinical uncertainty in primary care that drives referral has a low
detection of urothelial cancer and indeed other definitive clinical conditions but with universal use
of an invasive investigation. In this scenario test specificity is not a valid performance metric for
assessing alternatives, since the false positives identified by the test would be evaluated under the
current pathway anyway. Therefore a biomarker diagnostic that has a high NPV with high sensitivity
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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could perform confidently as an effective filter to referral, interrupting the default flow to an
invasive and a low yield diagnostic pathway.
5. Economic considerations
Given that this Tier 3 assessment is evaluating the implications of trialling a novel genomic based
technology and of exploring and testing the NHCs ‘pull and embed’ strategy, the economic
assessment has been limited to an estimate of the resource utilisation of the current model of care
and the potential impact on resources of the use of Cxbladder Triage.
Until further evaluation work on the performance and benefits of Cxbladder Triage is completed it is
difficult to reliably model likely resource impacts as estimates of performance and costs are
uncertain. It is unknown what level of change in the model of care might be achieved by introducing
this diagnostic tool and therefore the value and impacts to the sector that this type of intervention
might provide. Nor can the commercial cost of the test be known at this stage. Therefore the
estimate based on this economic analysis are preliminary and may be refined as evidence specific to
the proposed indication becomes available.
5.1 Methods
Data & Analysis
Data informing this analysis were obtained from:
New Zealand Cancer registry
Ministry of Health Analytical Services
Burden of Disease Epidemiology, Equity & Cost-Effectiveness Programme (BODE³)
Private providers of radiological services
Laboratory services providers
Data were analysed by the NHC Executive.
5.2 Use of diagnostic resources
Primary care
Options to confirm or check for haematuria in primary care include simple dipstick urinalysis or a
formal laboratory urine sample for microscopy and culture. Further investigation may include blood
tests, other urinary tests and radiological investigations. There are no available New Zealand data
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
showing the proportion of patients that are investigated further. International data are limited but
may be similar to New Zealand.
Estimating how many people present to primary care services with haematuria requires estimates of
incident cases who present to services either symptomatic reasons or by active detection despite a
lack of symptoms. Prevalence data, measuring how common haematuria is in a surveyed population
at a point in time, does not provide the rate of people present to clinical services. Individuals in
these studies are actively identified, may be asymptomatic without intention of accessing health
care services. International incidence data on haematuria in primary care is sparse and of better
quality for the presentation of macroscopic haematuria than microscopic haematuria. Available
estimates for adult populations with macroscopic presentation are of 250/100,000 per year from a
large primary care dataset (18) and 488/100,000 per year from a smaller prospective study(19). An
estimate for the presentation of either microscopic or macroscopic haematuria is 400/100,000 per
year. (19) The proportion of patients with microscopic haematuria to all haematuria presenting in
primary care is not clear though was 85% in a small US study.(20) By the time patients reach
secondary care the proportion is about 50%.
Estimates for the number of adults presenting in primary care annually with haematuria is subject to
a wide range. Based on an estimate of the incidence of macroscopic haematuria of 250/100,000 per
year, a conservative estimate for the presentation of all haematuria of 500/100,000 per year would
indicate that about 17,000 adult patients present with haematuria annually in New Zealand of which
half would be microscopic. Alternatively, if microscopic haematuria made up 85% of the haematuria
presentations (20) then the number could be more like 48,000 patients per year of which microscopic
would be about 41,000. These patients will included the spectrum of underlying clinical conditions,
some of which will be more readily identified than others. As indicated previously a significant
proportion of patients will not have a final specific diagnosis and the proportion with underlying
malignancy is low.
A small US study examined the electronic health record (EHR) of patients in primary care and of
hospitalised patients who presented with invisible (microscopic) or visible (macroscopic) haematuria.
Patients were excluded if they were already under the care of an urologist, receiving chemotherapy,
or had been recently hospitalised or catheterised. There were 449 included patients, of whom 82%
were female. Microscopic haematuria was present in 85% of the patients, and 57% of all patients
had additional symptoms. 18% of cases were referred to a urologist. Investigations included
cystoscopy (9%), imaging (36%), repeat urinalysis (63%) and urine culture (62%). Imaging was more
common in patients with macroscopic haematuria (42%) than others (34%).(20)
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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In another US study of men aged 35 and over and women aged 55 and over with asymptomatic
haematuria detected during a primary care health check, 99% of patients had follow-up urinalysis
within three months. Within 12 months, 13% had received an intravenous urogram(IVU) and 8% had
received cystoscopy.(21)
US data also shows marked variation in the frequency of investigation. The intensity and variation in
assessment of haematuria has been evaluated in a US health care provider across 19 clinics in both
primary and secondary care. Of 2,455 patients aged 40 or more with a first diagnosis of haematuria,
cystoscopy was performed in 13.7%, and abdomino-pelvic imaging in 13.9%. There was marked
variation in the frequency of investigation across the clinics, with a range for receipt of cystoscopy of
between 1% and 16% and for imaging of between 2% and 19%.(22)
Referral for specialist assessment
Published primary care guidance for the management of haematuria identifies the features of
patients to be referred, after certain diagnoses are excluded and certain investigations performed.
Urinary tract imaging and urinary cytology are recommended, though even with negative results
onward referral for specialist assessment in patients with a baseline high risk of urothelial cancer is
recommended. Patients with macroscopic haematuria with factors indicating higher risk of urothelial
cancer, when other causes have been excluded, should be referred for cystoscopy.(23) Similarly, when
microscopic haematuria is persistent and alternative diagnoses have been excluded, further
investigation, including radiological imaging and cystoscopy is recommended taking into account
other risk factors such as age.(23) Persistent microscopic haematuria is defined as positive testing on
two or three occasions seven days apart(23) or as two out of three positive dipstick tests.(24)
A significant proportion of cases are referred without a definitive diagnosis in primary care (18) and
remain undiagnosed after investigation in secondary care.(5, 6, 10, 11) This indicates that referral is
partly driven by clinical uncertainty and features that trigger this referral are not known. The clinical
features of patients referred to secondary care clinics where no prior investigation is reported
include of the extremes of age, both visible and invisible haematuria and about one-third being
female and two-thirds male.(6, 7, 10)
Secondary care
There may be further imaging in secondary care. Some patients will have been referred directly to
secondary care based on suspicious clinical features without additional imaging; others may need
imaging to define the renal tract more clearly after preliminary primary care imaging. Patients
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
referred to secondary care who are assessed as having a higher risk of malignancy will have
cystoscopy performed.
In a report on an Australian secondary care haematuria clinic, all patients had cystoscopy and
computerised tomography (CT), the preferred imaging modality.(10) In the UK, one haematuria clinic
investigated all patients with visible haematuria with ultrasound and either IVU or CT urogram
imaging of the upper tracts; and all patients had cystoscopy performed.(25) Another UK haematuria
clinic initially investigated all patients with ultrasound, plain X-ray and cystoscopy. If an abnormality
was detected, IVU or CT was performed; and IVU was performed if there were negative initial
investigations but persistent haematuria.(6) 44% of the patients in this study had abnormal first line
investigations, and about half of these had CT urogram and half IVU. 45% of those with normal first
line investigations (25% of total) had persistent haematuria. In total, 69% of the patients had further
imaging beyond the baseline plain X-ray and ultrasound.
Variation in the level of referral in New Zealand is not known. However, as noted above, a US
provider shows marked variation in the investigation of patients with haematuria across clinics, not
thought to be explainable by clinic geography.(22) There were differences in proportions of
cystoscopy, which could feasibly be partly explained by differences in referral to urologists.
5.3 Estimated resource use for current diagnostic model of target population
The initial assessment in primary care of patients presenting with microscopic haematuria who are
eventually referred to secondary care is assumed to comprise some or all of the following
components.
The initial steps are common to all patients presenting with haematuria and consider the clinical risk
factors and findings and form the differential diagnoses. A diagnosis may demonstrate a clinical
condition to explain the presentation, such as urinary infection, and negate the need for continued
investigation. Risk stratification is partly based on the presence of macroscopic versus microscopic
haematuria. As part of this assessment haematuria is confirmed with simple dipstick urinalysis and
proteinuria detected if present. All patients have a mid-stream specimen of urine sent for
microscopy and culture and have blood tests to check renal function and full blood count. In the
situation of microscopic haematuria, persistence is confirmed with one or more subsequent
urinalyses.
It may be assumed that all patients with microscopic haematuria who are eventually referred to
specialist assessment have renal tract ultrasound performed in primary care. There are however
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
reasons to think that this may not be the case. For example, patients considered to be at high risk of
urothelial cancer, for example through a combination or age, smoking history and occupation, may
be referred directly to urological assessment. Also, there may be incomplete availability of imaging
in primary care. The patient may need to pay for the examination, which may act as a barrier and so
not be done prior to referral. On the other hand, the clinical process to exclude non-urothelial
cancer conditions to explain the presentation of microscopic haematuria may be informed by
radiological investigation.
It may be assumed that all patients have urinary cytology performed. Cytology is recommended in all
higher risk patients with asymptomatic microscopic haematuria(26) or staged after negative imaging
in patients aged over 40 years.(23) The number of urine specimens required is not clear though three
samples is considered optimal(27) but this is not a common practice, likely because of cost and
convenience.(28) In a retrospective analysis of cytology samples used to assess patients with
microscopic haematuria 75% of patients had one sample and the average was 1.7 samples per
patient.(29)
In primary care it is assumed that each patient will be seen twice by the GP, acknowledging the
verification of persistence of microscopic haematuria, and that the basic blood tests and laboratory
urine analysis are performed. The cost for the above is estimated at $118. The cost of urinary tract
ultrasound is assumed to be $225. It is assumed that each patient has a single urinary cytology test
performed acknowledging that the use of the test is incomplete and that the appropriate number of
tests per patient is unclear. The cost of cytology is assumed to be $69 per patient.
The resources used in the secondary care investigation of haematuria are assumed to be $1,166 per
patient. It is assumed, based on the international experience of haematuria clinics that investigate
patients who have presented with macroscopic and microscopic haematuria, that assessment of the
average patient comprises the following:

all have a cystoscopy

69% of patients have further imaging additional to ultrasound because of abnormal results
of initial tests or because of persistence of haematuria after negative initial tests

55% of those who have further radiology have an IVU and 45% have CT urogram(6)
Table 5 shows the costs and sources for the above components of assessment.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
Table 5: Procedure costs for investigation
Procedure
Full blood count, electrolytes
Cost
($)
25
and creatinine
Source
Average cost from
laboratory providers
Canterbury Health Laboratory9
Waikato DHB7
Labtests8
Specimen to laboratory for
23
microscopy and culture
Cost from private
laboratory
GP visit
35
The Burden of Disease
Epidemiology, Equity and
cost-Effectiveness
Programme (BODE3).
Renal Tract Ultrasound
225
Average of range of
Canterbury Health Laboratory9
Labtests8
Broadway Radiology, Palmerston North10
available prices of sourced
private radiology providers
Urinary cytology
69
Average cost from
Canterbury Health Laboratory8
laboratory providers
Waikato DHB11
Labtests12
CT urogram
Intravenous urogram
850
400
Average of range of
available prices of sourced
private radiology providers
Broadway Radiology, Palmerston North10
Estimated cost of multiple
abdominal X-rays and
contrast media
Broadway Radiology, Palmerston North10
Christchurch Radiology Group13
Pacific Radiology, Wellington14
Christchurch Radiology Group13
Pacific Radiology, Wellington14
First Specialist Assessment –
Urology
266
Ministry of Health
National Price
Code S70002
Urology cystoscopy
484
Ministry of Health
National Price
Code S70005
7
http://www.waikatodhb.govt.nz/lab/
8 http://www.labtests.co.nz/index.php?option=com_wrapper&view=wrapper&Itemid=219
9
http://www.labnet.health.nz/testmanager/index.php?fuseaction=main.DisplayTest&testid=961
10
http://broadwayradiology.co.nz/service-fees.html
11
http://www.waikatodhb.govt.nz/lab/
12
http://www.labtests.co.nz/index.php?option=com_wrapper&view=wrapper&Itemid=219
13
http://www.christchurchradiology.co.nz/assets/files/QM70-Fee-Synopsis-01.pdf
14
http://pacificradiology.co.nz/services/prices/
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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Cost of model of care for diagnosis
For the current model of care where 1,600 patients (and the alternative of 3,600 patients) are
assumed to be referred for specialist assessment following presentation with microscopic
haematuria the costs of diagnosis can be considered for primary and secondary care assessment.
In primary care assuming that all patients have the urinary tract ultrasound and cytology performed
after the initial assessment the total cost is $0.7 million (and $1.6 million for the alternative of
3,600). For secondary care assessment the cost is $1.9 million (and $4.3 million for alternative test
population) giving an estimated total of between $2.6 million to $5.9 million.
5.4 Utilisation of Cxbladder Triage
The use of Cxbladder Triage offers an alternative model of care for the diagnosis of urothelial cancer.
The discussion of the following scenarios assumes, as outlined above, the perspective of 1,600
patients with microscopic haematuria (and an alternative of 3,600) who are referred for urological
assessment in secondary care. For this population it is assumed that 4% (5, 6, 12) have bladder cancer
and of which 94% are of the urothelial histological type.
The point at which the diagnostic is used in the model of care can be considered under alternative
scenarios that have different potential implications for diagnostic sequencing and accuracy and for
resource use.
1. Most conservatively it can be assumed that the above current model of care will remain
constant and that Cxbladder Triage will be additional and used just prior to the point of
referral to secondary care. In this way current diagnostic methods will remain, the use of
Cxbladder Triage will add an additional step and patients identified as not needing onward
referral will result in the reduced use of resources in secondary care.
2. Or it can be assumed that Cxbladder Triage will be used prior to or instead of cytology after
radiological imaging has been performed. Urinary cytology has a low sensitivity for
detecting urothelial cancer.(5, 30, 31) Cxbladder Triage may be an effective substitute and so its
use would complement the diagnostic model, may remove the cost of urinary cytology and
still identify patients not needing onward referral to urology services and reduce the use of
secondary care resources.
3. Or it can be assumed that Cxbladder Triage will be used immediately after initial assessment
prior to the use of imaging. The use at this point would potentially simplify the diagnostic
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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model for primary care and reduce the need for a diagnostic intervention for which there
are some barriers to access.
Scenario 1 may be considered the most likely to be implemented. As the evidence base for the new
diagnostic develops, as it operates in parallel with urinary cytology, it may demonstrate that the
performance of Cxbladder Triage is not enhanced with the additional input of urinary cytology
results. Scenario 3 may be less feasible to implement. Imaging modalities are also used to diagnose
conditions other than urothelial cancer that are explanations for haematuria. Potentially in those
patients with a positive Cxbladder Triage test result, and so are referred on immediately, the need
for imaging would be deferred, whereas those with a negative test result would proceed to imaging.
The use of Cxbladder Triage earlier in the diagnostic model of care has the potential to increase the
size of the target population for testing. If this was to occur it generates a risk of increasing patients
being referred for further investigation. As the testing population increases in size the prevalence of
urothelial cancer in the test population falls. With this change the PPV of the diagnostic falls with a
greater number of positive tests necessitating referral but an increase in false positive test results.
5.5 Factors to consider regarding the implementation of Cxbladder Triage
into routine clinical practice
Cxbladder Triage requires validation of its diagnostic performance and evaluation of its clinical utility
in the appropriate setting.
The currently known performance of Cxbladder Triage has been assessed in an alternative setting
and population group to its proposed clinical application, namely in secondary care in patients with
macroscopic haematuria. In order to generate confidence in its use its performance needs to be
validated in the primary care setting in patients with microscopic haematuria. The actual
performance of the diagnostic, its negative predictive value and ability of rule out urothelial cancer
need to be generated in the realistic clinical setting.
The composite diagnostic incorporates clinical data to generate a diagnostic outcome. The reliability
of collection of these data for input and how data quality impacts on the diagnostic test reliability
would be a beneficial aspect of an evaluation. The best use of the clinical factors of the diagnostic
algorithm may be further refined with greater analysis of the clinical input data.
The collection of the urine sample for analysis has to be done fulfilling certain quality control criteria
and samples may be collected in the medical setting or in the patient’s home also requiring a
balanced assessment of patient utility. The reliability of sample collection, in conjunction with the
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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impact of sample travel from rural areas may have an impact on sample quality control and so
overall performance and will be important to assess providing an indication of acceptability to
participating patients.
Further evaluation provides an opportunity to identify how common non-urothelial cancers are in
patients who present with microscopic haematuria. Additionally, clinical data on patient
presentation may inform factors that differentiate these cases from urothelial cancer and allow an
assessment of Triage’s performance in the detection of the much less common non-urothelial
cancers.
The performance of Cxbladder Triage can be assessed further in its relationship with other
diagnostic modalities, such as urinary cytology and imaging, to elucidate whether it has the potential
to replace other current investigations rather than be used as an additional option and so provide an
opportunity to simplify the diagnostic model of care as well as improve its effectiveness.
The potential of Cxbladder Triage is to improve clinical outcomes and improve the use of diagnostic
resources. The current understanding of the diagnostic model of care is limited and so an evaluation
of the current components and activities would inform the potential system impact of Cxbladder
Triage if it is found to have suitable diagnostic performance.
Some patients with early stage urothelial cancer, plus non-urothelial cancer will not be detected at
first testing who under the current model would have been detected. Understanding the features of
these patients and how they behave clinically will inform how they can be appropriately identified
subsequently, promoting clinical safety.
The impact of a new diagnostic is dependent not only upon its performance but also on its
acceptability to clinicians. It will be important in due course to assess whether its use is clinically
acceptable, and so whether when used the information it provides is acted on by clinicians, and so, if
it has true clinical utility.
5.6 Potential Benefits of Cxbladder Triage
The following sections consider the potential effectiveness and efficiency from the perspective of
both patients and funders. With reference to the estimate of current diagnostic utilisation and costs
potential resource impacts of the introduction of Cxbladder Triage are considered. The data are
considered from the perspective of scenario 1 described above and with respect to the estimated
target population sizes; 1,600 and the alternative of 3,600.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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Patient benefits:
The key benefit of Cxbladder Triage to the patient is a faster diagnosis. The NHC estimates that 698
patients of the 1,600 each year (or 1,571 of 3,600 patients), would have a negative test result and
have a shortened time to diagnosis; these patients are likely to be diagnosed within a week. These
patients would otherwise have had to wait up to 4 months to be seen by a urologist (four months is
the Elective Services Patient Flow Indicators (ESPI) targets reported by the Ministry of Health).15
There would not necessarily be a difference in time to diagnosis for the patients who test positive
but a reduction in referrals overall may aid more prompt assessment of those still needing referral.
The proportion of patients that avoid the necessity of referral may be higher. Based on the findings
of the small microscopic haematuria cohort tested in the published literature (4) up to 80% could
have negative diagnoses. If that was the situation then the number of patients not going on to
secondary care assessment could be nearly double the numbers given above. Similarly, the potential
positive impact on urology services and reduction in costs could be increased by almost a factor of
two at this level of negative test results.
Additionally, for these patients there would no longer be the need to travel to a hospital
appointment and its associated inconvenience plus the avoidance of invasive investigation and its
risks of complications
Under the assumptions Cxbladder Triage has a NPV of 99%. A diagnostic that has a high negative
predictive value can provide confidence in the negative result and certainty regarding concern of
bladder cancer to the patient being investigated.
Clinician Benefits:
With the addition of Cxbladder Triage to the diagnostic model of care GPs will maintain involvement
in the diagnostic process allowing greater clinical continuity within primary care. At the same time a
test with a high NPV will offer confidence for the clinician in the decisions made and support the
need for clinical safety. Despite the high NPV (0.99) of the 1,600 patients considered, about six of the
698 (or 12 of the 1,571) with a negative test result will have a bladder malignancy. There is an
expectation of ongoing monitoring despite negative investigation. In patients who have been
investigated and no specific cause has been found monitoring for new symptoms, of blood pressure,
cytology and urinalysis is recommended annually or six-monthly for two to three years, with further
referral in the event of positive findings.(23, 26) It is reasonable to expect that those with initially
15
http://www.health.govt.nz/system/files/documents/pages/december-2014-all-services-report.pdf
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undetected cancer will remain symptomatic, present for review and be referred subsequently. So,
some additional consultations with GPs may result.
Urologists will have some time freed up from reduced first time appointments. NHC estimate there
will be 698-1,571 fewer First Specialist Assessment (FSA) each year, this is about a 3-6% reduction
(based on 25,000 urologists FSAs in the year ending 2014). Freeing up urologist time:



will enable urologists to focus their attention on higher risk patients
may result in reduced waiting times and assist hospitals meet their Elective Services Patient
Flow Indicators (ESPI) targets
may improve targets regarding time to diagnosis of cancers.
Additionally, as fewer patients will be accessing secondary care, there will be a reduction in imaging
resource utilisation. There will be 480 (or 1,080 for the alternative estimate) fewer IVUs or CT
urograms performed. The reduction in demand for these services will reduce demand pressure on
radiological services. As a result waiting times overall for those patients still needing to access these
diagnostic services could reduce.
Cost resource impact:
Using the reported performance settings for Cxbladder Triage, with a sensitivity of 95%, and
specificity of 45%, then 44% of cases (698 of 1,600 or 1,571 of 3,600) would not be referred after
initial testing. Under scenario 1 above where Cxbladder Triage is employed when otherwise the next
step would be referral there would be a reduction in costs in secondary care. This could therefore
potentially equate to a reduction in direct diagnostic pathway costs of between $0.8 million and $1.9
million per year. The above does not account for the cost of the Cxbladder Triage test or the
proportion of those with negative initial results who would go onto specialist assessment because of
ongoing symptoms and concern for false negative results.
If Cxbladder Triage is used as a substitute for urinary cytology then there would be an additional
reduction in resource use of about $0.1 million($0.2 million if 3,600 patients) though this could be up
to $0.3 million($0.6 million for 3,600 patients) if patients in fact are receiving optimal frequency of
urinary cytology samples.
Summary
The analysis above provides an estimate of the value from Cxbladder Triage. Based on the
information currently available, it is estimated that:
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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
Continuity of care will be improved for patients and care delivery will be more convenient

Clinical care will be enhanced in primary care, and delivered in a more timely manner

Approximately 40% of patients will avoid the need for referral to second care for invasive
investigation

Reduction in referrals will potentially release urological specialist and diagnostic resources
and result in more timely access to services for those who still require referral.

Between Around $0.8 and $1.9 million of health care costs may be avoided

If closer to 80% of patients avoided referral, as indicated in the small initial microscopic
haematuria validation cohort, the benefits could be increased by a factor of two.
These estimates are preliminary as they are based the performance of Cxbladder Triage in a
different setting to that proposed. The value of the current estimate is that is helps inform the
potential value of Cxbladder Triage in the primary care setting for those with microscopic
haematuria. In order to create more confidence in the estimated benefits of Cxbladder Triage
specific evidence of Cxbladder Triage ability to detect bladder cancer in the proposed population
group is needed.
6. Societal and ethical considerations
6.1 Methods
The formal research questions for assessing societal and ethical implications were:
In New Zealand what are the societal and ethical implications of the introduction and application of
a novel genomics based technology?
Data informing this analysis were obtained from:
Ministry of Health Analytical Services
New Zealand Cancer Registry
Search strategy
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6.2 Higher order considerations
Analysis of the societal and ethical considerations of pulling novel genomics based interventions into
the New Zealand health system raised a number of issues about which there is no applicable
evidence.
There is information provided at the end of this section on the potential ethical impact of test
uncertainty, such as false negatives and false positives and likely improvements in equity and
timeliness of access. However consideration of this new diagnostic intervention raises a number of
higher order questions that would need to be explored through a carefully constructed Innovation
Evaluation.
For example:

Will current informed consent processes provide adequate protection for patients and
clinicians?

What are the informed consent processes necessary when genomic information collected
for one purpose may be used for another clinical or commercial purpose?

Given the diagnostic value of the genotypic and phenotypic composite algorithm is reliant on
the veracity of the phenotypic data provided by the patient, what are the implications for
patient behaviour and personal responsibility for the outcomes of testing? What is the role
and responsibility of the clinician?

Who owns the genomic data? Does the patient retain ownership and therefore decision
rights around the use of their data to inform the improvements of this composite algorithm
or other innovations?

What are the patient’s ownership and decision rights when their information is used to
improve a tool that is then used internationally? Or conversely what are the responsibilities
of the NHC when considering the introduction of a composite tool developed using a nonNew Zealand population?

What are the issues in ensuring the ownership and privacy rights of different populations,
particularly those with poor health literacy?
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
Are there any additional ethical and societal implications of having genomic data stored in a
patient’s file particularly when New Zealand is moving to a shared medical record model of
information management?

Is it possible, and if so how, to balance the “public good” outcomes sought by the NHC in
pulling new technology into the system with the imperatives of commercial return and
protection of intellectual property of technology developers?

What is the impact on direct-to-consumer marketing for a diagnostic for which the sample
could be collected in the home and then be analysed in a laboratory outside of the
mainstream community laboratory services?
These are just some of the “known” higher order questions when considering this type of innovation
pull. There are likely to be a significant number of unknown issues that will emerge as further work is
undertaken on this topic.
6.3 What is known - False test results
False negatives
When a new novel diagnostic replaces an established diagnostic method, there is concern about
patients who receive a false negative test result. That is, where a diagnostic result is negative,
indicating they do not have the condition, but in fact they do and the condition would have been
detected by the standard investigation. This is an appropriate concern with bladder cancer. Early
stage bladder cancer is treated by tumour removal and instillation of therapeutic agents into the
bladder. For those who present with or progress to muscle invasive bladder cancer (stages T2 ,T3
and T4), treatment is with radiotherapy, chemotherapy and radical cystectomy,(32) and there are
worse patient outcomes
The performance of Cxbladder Triage is based on the genomic based components of Cxbladder
Detect that has an overall sensitivity of 82% for TCC. This includes a sensitivity of 68% for stage Ta
disease, and 100% for other stages. Therefore, the false negative cases are patients who have Stage
Ta cancer which is a lower stage of disease. In addition it is not known how Cxbladder Triage
performs in the detection of non-urothelial disease. However, the biomarkers used do reflect
pathological change in cell turnover and so theoretically could detect non-urothelial disease.
There is no known data on the risk of disease progression for people with missed diagnoses, but we
can extrapolate from data on patients who have been diagnosed, staged and treated. Studies of
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
treated patients show that several factors affect disease recurrence and progression to invasive
bladder disease, including grade and stage of disease and number of tumours.(33) Risk of progression
is: (34)

0.2% after a year for lowest risk patients, including those with low grade disease and
stage Ta;

about 1% at 12 months post-treatment for those with carcinoma in-situ;

9% risk of progression to invasive disease at five years for patients with Ta or T1 disease
without carcinoma-in-situ (CIS) treated solely with transurethral removal of bladder
tumour (TURBT);

between 7 and 40% at 5 years for patients with Ta or T1 disease with CIS.
These data suggest that, in low risk disease, a delay of a few months would probably not be
associated with disease progression to a state where treatment options are fundamentally changed.
However, the impact on clinical outcomes of a delay of, for example, a number of months in
diagnosis of bladder cancer should also be considered in the context of current practice. Time to
diagnosis includes the time from presentation in primary care, through initial investigation, referral
to secondary care and waiting time until the specialist assessment. If the introduction of an
alternative diagnostic pathway reduced the overall time to diagnosis, a delay of some months for a
subset of patients may not make a significant difference from the status quo.
Further review in the diagnostic model of care of patients with ongoing symptoms, despite a
negative Cxbladder Triage result, would be expected and ensure detection of false negative cases
with access to appropriate further assessment.
Concern over non-identification should also acknowledge that in the current diagnostic pathway for
bladder cancer, cystoscopy (considered the gold standard), does not have a 100% sensitivity for the
detection of bladder cancer.
False positives
A positive Cxbladder Triage result that suggests further Investigation may cause anxiety for the
patient. The consequent referral to secondary care services and further investigation may increase
this anxiety and cause inconvenience for the patient, and absorb secondary care health resources. It
is important to acknowledge that a ‘further investigation’ result, does not infer a positive diagnosis
of urothelial carcinoma.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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At least half of the people who receive positive test result with Cxbladder indicating the need for a
‘further Investigation’ will not actually have urothelial cancer and so it will be important to ensure
that patients are fully informed about the meaning of their test result. This should be balanced by
the fact that under the existing haematuria diagnostic pathway, all patients currently referred to
secondary care for urological assessment are considered as potentially having urothelial cancer with
associated waiting times and anxiety.
6.4 Equity and acceptability
Appropriate avoidance of referral to specialist services by bringing diagnostic services closer to the
patient would be expected to be acceptable to patients and practitioners. Providing investigations in
the primary care setting that appropriately avoids the need for referral can overcome a barrier to
access that acts more against groups with higher health needs. Additionally the change has the
potential to reduce barriers to care that are demonstrated by the rate of non-attendance for
outpatient appointments. Given that non-attendance is more common for Māori and Pacific
peoples, then providing appropriate care in the primary care setting could contribute to
improvements in equity of access to care.
Clinical acceptability of Cxbladder Triage will be enhanced with effective performance in detecting
TCC cases and the means of identification of originally false negative patients.
7. Feasibility of adoption
7.1 Methods
The formal research question for assessing feasibility of adoption was: Is the adoption of Cxbladder
Triage feasible in the New Zealand public health care system?
7.2 Workforce
Implementation of Cxbladder Triage in primary care would require education of clinicians regarding
its appropriate use for testing purposes, interpretation of results and the necessary process and
administrative requirements for its effective and consistent use in the target population. There is the
opportunity for the release of specialist secondary care resources that would allow redirection into
other areas of clinical need.
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7.3 Infrastructure
Cxbladder Triage diagnosis is not provided through the standard community diagnostics laboratory
contract. However, testing is accessible to primary care providers. To perform the biomarker analysis
currently, the patient’s urine sample is added to a transport buffer sample and then sent to the
Pacific Edge laboratory, where it is analysed. The final result is then generated through application of
the proprietary algorithm to the individual biomarkers data from the diagnostic results. The testing
infrastructure therefore sits outside of the standard diagnostic laboratory system, and Pacific Edge
owns the intellectual property for the urine sample transport buffer and the results algorithm.
Introduction of Cxbladder Triage to routine practice would therefore require review of current
infrastructure for any changes required.
7.4 Policy congruence
The potential to change the diagnostic model is in keeping with the policy framework of Better,
Sooner, More Convenient services in the community.
From a patient perspective, a change to the diagnostic model has the potential to keep more care
within the primary care setting with more immediate assessment and conclusion to the diagnostic
process. Non-attendance for out-patient clinic appointments is a significant issue across all clinical
specialities, and Māori and Pacific peoples have a higher rate of non-attendance than other ethnic
groups. Changing the diagnostic model has potential for avoiding assessment in secondary care that
some people find more difficult to attend.
Currently, further investigation for bladder cancer requires a diagnostic cystoscopy. This
investigation is invasive and uncomfortable, and so appropriate avoidance would lead to improved
patient experience.
The appropriate reduction in demand for urological assessment services for the area of bladder
cancer will allow for the redirection of resources to other areas of clinical activity and allow
improved access to care for other patients needing specialist assessment.
7.5 Patient factors
The ability of Cxbladder Triage to translate patient information into a calculation of cancer risk is
determined in part by the level of information accuracy and detail. Patients sometimes do not have
detailed recall of their history, particularly given the age group of patients presenting with
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
haematuria; or are sometimes reluctant to share the full extent of some health behaviours such as
smoking.
Education and support of the patient to understand the need for full disclosure for this tool will be
essential. Additionally, if the patient is to be responsible for the collection storage and
transportation of the urine sample, training and support will be required to ensure the correct time
sensitive process is followed.
8. Opportunity for Learning
There is little data to inform the use of biomarker testing in primary care as a gatekeeper test for
referral to secondary care, and none specific to New Zealand. There is also very little accurate data
from which to determine details of current practice. This assessment is therefore necessarily based
on extrapolated data, assumptions and estimates which cannot be robustly validated.
Biomarker testing in general and Cxbladder Triage in particular are part of a developing field of
knowledge and practice. Although clinical trials do not provide all the data for a fully informed
decision, there is the opportunity to bring a public health perspective to the research to ensure that
future research collects and reports necessary data.
8.1 Development of the evidence base
Currently the evidence for the performance of Cxbladder Triage has been developed on a patient
population that has been referred to secondary care because of the presence of macroscopic
haematuria. The genotypic features of the tumours have been allied to the clinical features to
develop the algorithm. The intention is for the diagnostic to be applied in an alternative clinical
setting and lower risk population from its development.
Validation
The next step is to demonstrate the performance of the diagnostic in the appropriate primary care
population. A validation study needs to be performed on patients identified in primary care who
present with microscopic haematuria. The design of this trial would be to apply the new diagnostic
test to patients undergoing routine care who would follow the standard diagnostic procedure
allowing clear clinical outcomes to be identified. The performance of the Cxbladder Triage could
then be assessed against standard care to determine its performance in the primary care setting.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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Evaluation
Beyond the clinical performance of Cxbladder Triage the impact on the diagnostic model would need
to be evaluated. An Innovation Evaluation would be able to demonstrate whether the use of the
Cxbladder Triage actually changed clinical diagnostic behaviour and delivered the outcomes
expected in terms of referral and resource use that are predicted from the current knowledge of
clinical performance. The design of the trial would compare the standard diagnostic model to the
alternative and collect both clinical and resource outcomes for the target population. Such a trial
would demonstrate if the necessary components of the changed diagnostic model work.
Performing the validation step first to demonstrate the clinical performance of Cxbladder Triage
reduces the risk of doing a larger trial that has more objectives, that requires greater time and
resources but may not be underpinned by the necessary diagnostic performance. A step-wise
approach manages risk by first showing satisfactory validation performance before committing to
further investigation. However, the staged approach may then lead to slower progress to the final
conclusions.
The Innovation Evaluation needs to include a sample of patients that are representative of the New
Zealand population in order for the results to be considered reliable to be applied generally. The
sampling also needs to account for geographical and primary care delivery variation.
The Innovation Evaluation will allow for the assessment of quality control measures. The urine
specimen can be collected in the practice setting or at the patient home. Analysis of site of collection
and its impact on the satisfactory sample rate is an important consideration particularly in the light
of older patients, inevitably having other health conditions, being participants. Collection from more
remote geographical areas and its impact on the sample quality is also important.
The Innovation Evaluation could allow the evaluation of how well the clinical data operate within the
algorithm. Are there practical issues regarding data collection, whether data collection is complete
and whether the potential refinement of the factors such as age and smoking status improve
diagnostic performance, but possibly at the cost of reduced reliability of smoking history recall?
There is an expectation that the Cxbladder Triage will be used in patients who have undergone
preliminary investigation in order to exclude other potential explanations. The Innovation Evaluation
will be able to consider if this expectation is adhered to or whether additional patient management
system methods are required.
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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In view of the potential for clinical factors to stratify risk, there is the potential to analyse whether
the phenotypic components of the diagnostic operate to identify some patients at sufficiently high
risk of TCC to make the addition of the genotypic data unnecessary.
8.2 Development of experience with algorithm based diagnostics
The output from the Cxbladder Triage diagnostic is reliant on the mathematical analysis of the
multiple genotypic and phenotypic data inputs. Demonstration of the validation of the algorithm in
the case of Cxbladder Triage and learning how the method works could be of future relevance.
Future technologies that are reliant on similar algorithmic methods could be more reliably reviewed
in the light of experience gained with Cxbladder Triage.
8.3 Development of higher order experience
Cxbladder Triage provides an opportunity for the NHC, in collaboration with Pacific Edge, to develop
in four areas:

Improvement of its technical and system understanding of the introduction of genomic
based interventions,

How to pull technologies into the health system

How systems and models of care change when faced with novel innovation

If Cxbladder Triage provides a step change opportunity in the primary care diagnosis of some
bladder cancers.
There are both risks and opportunities to be considered around further developing the relationship
with Pacific Edge through trialling Cxbladder Triage, particularly how to structure an Innovation
Evaluation in a way that will effectively provide answers to the four points above.
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Mishriki SF, Vint R, Somani BK. Half of Visible and Half of Recurrent Visible Hematuria Cases Have
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
using Cxbladder Triage to rule out urothelial cancer
National Health Committee (NHC) and Executive
The National Health Committee (NHC) is an independent statutory body which provides advice to
the New Zealand Minister of Health. It was reformed in 2011 to establish evaluation systems that
would provide the New Zealand people and health sector with greater value for the money invested
in health. The NHC Executive is the secretariat that supports the Committee. The NHC Executive’s
primary objective is to provide the Committee with sufficient information for them to make
recommendations regarding prioritisation and reprioritisation of interventions. They do this through
a range of evidence-based reports tailored to the nature of the decision required and timeframe
within which decisions need to be made.
Citation: National Health Committee. 2015. Tier 3: Alternative investigation and management of
haematuria in primary care using Cxbladder Triage to rule out urothelial cancer.
Wellington: National Health Committee.
Published in August 2015 by the National Health Committee
PO Box 5013, Wellington, New Zealand
ISBN 978-0-478-44835-1 (online)
HP 6212
This document is available on the National Health Committee’s website:
http://www.nhc.health.govt.nz/
Disclaimer
The information provided in this report is intended to provide general information to clinicians,
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believe may be inaccurate, please email to NHC_Info@nhc.govt.nz
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The contents of this report should not be construed as legal or professional advice and specific
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National Health Committee – Tier 3: Alternative investigation and management of haematuria in primary care
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Any reference to any specific commercial product, process, or service by trade name, trademark,
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