4. The NSW CLEAR Study
Overview and Methodology
Provenance
• University of Oxford:
– Johannesburg Cancer Case Control Study. Professor
Valerie Beral
• University of Oxford / Peking Union Medical College:
– Million Deaths study. Professors Richard Peto, Bo-Qi
Liu (spouse control)
• Share some questions with 45 and Up study
5. The NSW CLEAR Study
Overview and Methodology
CLEAR Study Aims
1. To investigate the molecular and environmental risk
factors for cancer in NSW
2. Understand the relative importance of leading /
emerging risk factors for cancer in a local setting
3. (Future) Construct a „cancer cohort‟ study to investigate
the consequences of a cancer diagnosis
4. Develop a research platform between epidemiologists,
basic scientists and clinicians
6. The NSW CLEAR Study
Overview and Methodology
CLEAR Study Operations
Participation
– Consent
– Questionnaire
– +/- blood sample
Recruitment
− Targeted
− Non-targeted
Eligibility criteria
− Incident cases
− NSW resident
− > 18 years
7. The NSW CLEAR Study
Overview and Methodology
Case and Control Design
Male Case
Female Partner
Female Case
Male Partner
8. The NSW CLEAR Study
Overview and Methodology
A Good Control Group
• Representative of the background
population (if the cases are so)
• Comes from the same catchment area
as the case
• Would use the same hospital if they
became a case
1Breslow
and Day, Rothman, Schlesselman, Miettinen
9. The NSW CLEAR Study
Overview and Methodology
Recruitment Sites of Participants
Port Macquarie
Hospital
2%
Royal Prince Alfred
Hospital
2%
Liverpool Hospital
3%
HCF Health Fund
Registry
4%
St Vincents
Hospital
2%
Other
7%
Riverina Cancer
Care Centre
6%
SESIAHS ClinCR
41%
Cancer Council NSW
9%
SSWAHS ClinCR
24%
10. The NSW CLEAR Study
Overview and Methodology
Actual Numbers (see Data book, page 5)
Note: Cancer types with less than
N=20 are grouped under the Other
category
11. The NSW CLEAR Study
Overview and Methodology
Illustrative Numbers of Cancer Patients (18-79 years)
•
•
•
Now:
Link to NSW Central Cancer Registry
– Diagnosis, topography morphology and staging
Future:
– Deaths, Event and COD, [RBDM, ABS]
– Admitted Patient Data Collection
– Pathology records (negotiating)
– Dental records
– Medicare (negotiating) [MBS, PBS]
12. The NSW CLEAR Study
Biobank Collection Protocol
ACD Plasma
ACD Buffy coat
Serum
ACD - RT
SST - ~4⁰C
-80⁰C
Process
≤48hrs
13. The NSW CLEAR Study
Protocol Compliance
Samples received (n)
4500
82%
4000
3500
3000
2500
QUALITY REPORTING
• Delivery temperature
• Date/Time of collection
• Date/Time of processing
• Haemolysis score
• Short fill
2000
1500
1000
500
0
0
1
2
3 Days 4
5
6
7
>7
14. The NSW CLEAR Study
Biospecimen Quality Control
CCNSW Stability Study
• pre-analytic variation (t and time)
• 4 vacutainer types
• several molecular groups eg;
antibodies, cytokines, ncRNAs
Further enquiries:
verityh@nswcc.org.au
15. The NSW CLEAR Study
Application Process
Online Application
Data Access Coordinator
(practical feasibility check)
Expert Advisory Committee (EAC)
(peer review of all aspects of application)
Y/N
CLEAR Principal Investigator
Feedback to Applicant
16. The NSW CLEAR Study
Cost Structure
• Application Fee: $500
• Licence Fee: $20,000
• Linked data - additional fee: $3,000
• Preparation for linkage: $3,000
• Data cleaning: $100 per hour
17. The NSW CLEAR Study
Cost Structure
Application Fee: $500.00
Plasma and Serum: $20 per 500µl aliquot
DNA: $47.50 per 25 µl aliquot
Licence Fee applies if variables beyond minimum data set are
requested
Timing of release of aliquots may be dependent on quantities
requested and on other applications for the same product.
18. Smoking and Tobacco
The NSW CLEAR Study
Collaborator Meeting Day 1
Thursday December 5th, 2013
22. The NSW CLEAR Study
Our current work on Smoking/Tob.
Australia
• No contemporary
studies of risk of
smoking
• All estimates indirect
−Underestimate?
23. The NSW CLEAR Study
Our current work on Smoking/Tob.
The importance of local studies
Relative risk of developing lung cancer
(US Smoker vs. non-smoker)
Year of study
M
F
1959-1965
12
3
1982-1988
25
13
2000-2010
27
26
24. The NSW CLEAR Study
Our current work on Smoking/Tob.
Research Questions
1. Contemporary risks of smoking on
cancer in Australia
2. Add to evidence where causation
is inconclusive
• Bowel (IARC 100th Mono)
• Prostate
• Breast
25. The NSW CLEAR Study
Our current work on Smoking/Tob.
Cancer type
Study
Variable
OR (95% CI)
Women
Million Women
Study***
1.0
5.1
20.9 (12.0, 36.3)
31.7 (14.9, 67.7)
Never
1.0
1.0
Past
8.1
Current††
Cancer Prevention
Study**
1.0
Current†
CLEAR*
Never
Past
Lung cancer
Men
23.4 (19.6, 25.6)
Never
1.0
(3.1, 8.3)
(7.2, 9.1)
Past
Current
21.4 (19.7, 23.2)
* adjusted for age, socioeconomic status and migrant status
** adjusted for cohort, age, race and education level
***adjusted for recruitment site, age, body mass index, socioeconomic status, current alcohol
intake, physical activity, oral contraceptive use, menopausal status and hormone therapy use.
† current smokers are classified as those who still smoke or those who had quit smoking within the
previous five years from date of recruitment into study
† † current smokers are classified as those who were still smoking at time of recruitment into study
5.8
7.1
(2.9, 11.7)
(6.1, 8.2)
25.6 (21.7, 30.3)
26. The NSW CLEAR Study
Our current work on Smoking/Tob.
Cancer type Study
Variable
OR (95% CI)
Women
1.0
1.4
(1.0, 2.1)
1.4
(1.0, 1.9)
Current†
2.2
(1.5, 3.4)
4.9
(3.5, 7.0)
Never
1.0
1.4
(1.1, 1.8)
2.8
(2.2, 3.5)
Current†
JCCC****
1.0
Past
CLEAR*
Never
Past
Tobacco
related
cancers
Men
1.9
(1.6, 2.2)
4.6
(3.7, 5.7)
•adjusted for age, socioeconomic status and migrant status
•**** adjusted for age, education, smoking status and cooking fuel
† current smokers are classified as those who still smoke or those who had quit smoking within
the previous five years from date of recruitment into study
1.0
27. The NSW CLEAR Study
Our current work on Smoking/Tob.
A Typical Analysis (e.g. Stein et al 2008)
29. The NSW CLEAR Study
Hormones Questions
Hormone Exposure in Women
30. The NSW CLEAR Study
Hormones Questions
Hormone Exposure in Women (Cont’d)
31. The NSW CLEAR Study
Hormones Questions
Other related information captured in CLEAR
• Family history of breast and ovarian cancers
• Hysterectomy , oophorectomy, sterilisation
and pregnancy terminations
• Breast screening mammograms and Pap
smear test histories
32. The NSW CLEAR Study
Hormones Questions
Hormone Exposure in Men
36. The NSW CLEAR Study
Our current work on Hormones
Hormones and Breast cancer risk
Case-control analyses using data from
the NSW CLEAR study
PhD candidate – Usha Salagame
Supervisors – A/Prof Karen Canfell
A/Prof Freddy Sitas
Prof Emily Banks
37. The NSW CLEAR Study
Our current work on Hormones
Research Objectives
Estimating the risk associated with specific exposures
and comparing them with results from large
collaborative studies to validate the study design and
use of spouse controls
•
•
•
•
•
•
•
•
Age at menarche
Abortion
Age at first birth
Use of oral contraceptives
Breast feeding
Menopausal status
Parity
Family history
38. The NSW CLEAR Study
Our current work on Hormones
Research Objectives Cont‟d
Case-control analysis- MHT use and breast cancer risk
Analysis by
• current, past and ever use of MHT
• by duration of use
• type of MHT preparation
39. The NSW CLEAR Study
Our current work on Hormones
Why study MHT use and its
association to breast cancer?
• Increased risk of breast cancer due to menopausal
hormone therapy -established elsewhere in the world1,2.
• An estimation of the risks specifically in NSW among
Australian women through CLEAR study -contemporary
and local.
• Prior work suggests that much of the drop in breast
cancer incidence rates is due to the concurrent decline in
HRT prescriptions in Australia3.
1.Writing group for the Women's Health Initiative investigators. Risks and benefits of estrogen plus
progestin in healthy menopausal women: principal results from the Women's Health Initiative
randomised controlled trial. JAMA 2002; 288: 321-33.
2.Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the million
women study. Lancet 2003; 362:419-27.
3.Karen Canfell, Emily Banks, Aye M Moa and Valerie Beral. Decrease in breast cancer incidence
following a rapid fall in use of hormone replacement therapy in Australia.MJA 2008; 188:641-44.
40. The NSW CLEAR Study
Our current work on Hormones
Example of analysis: The Million Women Study 2003
41. Sun Exposure and Sleep
The NSW CLEAR Study
Collaborator Meeting Day 2
Thursday December 5ht, 2013
42. The NSW CLEAR Study
Sun Exposure and Sensitivity Questions
Outdoor UV Exposure
43. The NSW CLEAR Study
UV Exposure and Sleep Questions
Indoor UV Exposure
Sleep
44. The NSW CLEAR Study
Sun exposure and cancer risk
Sun Exposure and Internal Cancer Risk
Vitamin D hypothesis
-vitamin D deficiency may be a risk
factor for cancer.
45. The NSW CLEAR Study
Current evidence
Vitamin D and cancer risk
- Health Professionals Study (USA) 2006
46. The NSW CLEAR Study
Current evidence
Sun exposure and cancer risk:
NIH-AARP Diet and Health Study (2012)
47. The NSW CLEAR Study
Current evidence- NSW
Sun exposure and prostate cancer in NSW:
Prostate Cancer Care and Outcomes -Sun Study
(2012)
Table 1. Odds ratios for prostate cancer in quartiles of increasing
weekly hours of sun exposure
Odds ratio1 (95% CI)
Solar UV exposure
(Quartiles)
Q1
Q2
Q3
Q4
p-value4
1Adjusted
Weekly
1.00
1.3
(0.9,1.9)
1.5
(1.0,2.2)
2.1
(1.4,3.2)
0.007
for year of birth and sun sensitivity.
Weekend
1.00
1.4
(0.9,2.0)
1.6
(1.1,2.3)
5.6
(2.9,10.5)
<0.0001
48. The NSW CLEAR Study
Systematic review
Sun exposure, vitamin D and cancer risk (De Vries 2013)
• Almost all epidemiological studies suggest that sun exposure
is linked with risk of colorectal, breast, prostate, NHL cancers
• No associations between vitamin D and cancers of the
prostate and NHL.
• Prostate and NHL
“other sunlight potentiated and vitamin D independent pathways
i.e. immune modulation and circadian rhythm and folic
degradation may play a role”.
49. The NSW CLEAR Study
Sleep and cancer risk
Circadian Rhythm and Cancer Risk
"shift-work that involves circadian disruption" as
"probably carcinogenic to humans" (Group 2A)
- The International Agency for Research on Cancer
50. The NSW CLEAR Study
Evidence on sleep and cancer risk
Meta-analysis of the association between long sleep and risk of
cancer: Prospective Cohort Studies (Lu et al 2013)
51. The NSW CLEAR Study
Our current work on Sun Exp/Sleep
Sun exposure and cancer link in CLEAR
• Time spent outdoors
52. The NSW CLEAR Study
Frequency of Exposures
•
•
•
•
Places lived
Solarium use
Duration of sleep
Shift work
64. The NSW CLEAR Study
BMI/Phys Act
Research Questions
• Which cancers are associated with BMI in
Australia
• Are there differences
– between M&F
– Migrant groups
– BMI at different ages
– Pre and post-menopausal?
65. The NSW CLEAR Study
BMI/Phys Act
Possible analyses using CLEAR (Reeves et al, MWS 2008)
66. The NSW CLEAR Study
Alcohol
Alcohol
Smoking
Comment
-
-
Baseline – Methodological problems of ascertaining
former vs. never drinkers. Use co-morbidities as proxy?
+
-
Studies limited by statistical power. InterSCOPE shows
some associations
+
Adj or not
sp.
Association well established for numerous cancer types
+
+
Strong, consistent association – multiplicative
67. The NSW CLEAR Study
Current work on Alcohol: InterSCOPE, n=4000
68. The NSW CLEAR Study
Alcohol
• Which cancers are associated with alcohol
– Upper digestive, bowel, breast, …
• Interactions? With BMI, Smoking
• Alcohol dehydrogenase ($)
76. The NSW CLEAR Study
Our current work on Infect. Dis.
Research Opportunities
• Number of cancers caused by known infections in
Australia is small ~3%
• Still cause significant mortality and morbidity
• Infections can be removed
• Infectious disease discovery not over yet
− Bladder, H&N, Prostate?, haematological, [skin] …
o Spinoffs: diagnostics, blood supply, vaccine,
chemotherapy
• Add other studies that can increase sample sizes
77. The NSW CLEAR Study
Our current work on Infect. Dis.
Research Questions
• Questionnaire correlates
– Are specific lifestyle factors correlated with specific
cancers?
• Sex behaviour
• Tattoos
• Piercings
• IV drugs
• Prostatitis
• Blood transfusion
• Organ transplant
78. The NSW CLEAR Study
Our current work on Infect. Dis.
Research Questions
• Pathogen-related screening tools developed for
– cervical cancer (HPV screening)
– liver cancer (hepatitis B, C)
• No screening tools for
– H&N, male genital, stomach, …
• Suspected infectious cause for several cancers
yet to be unravelled
79. The NSW CLEAR Study
Our current work on Infect. Dis.
List of Pathogens – DKFZ ~100
• HPV1-107
• L1, E2, E6, E7
• SV40
• Polyoma BK, JV, MC
• H.pylori 21 proteins
• Hepatitis B, C
• Herpes
I,II, CMV, EBV
• Retroviruses
• Luminex platform
• Several under
construction
• High throughput
• ~AU$15 per sample, 50
results
• 0.2ml serum
80. The NSW CLEAR Study
Our current work on Infect. Dis.
Types of Research Questions
• Serotype distribution of HPV in
background (controls) and in cases of
H&N, cervix, other genital sites (n?)
• Improving predictive value of serological
markers
• Existing pathogen, new disease
• New pathogen?
81. The NSW CLEAR Study
Our current work on Infect. Dis.
Illustration of Results – New Pathogen e.g. Sitas 1999
1.
2.
3.
4.
How common?
How dangerous?
Which cancers?
Which cancers
NOT?
82. The NSW CLEAR Study
Our current work on Infect. Dis.
Many pathogens, one cancer: InterSCOPE: HPV
serological markers and OSCC
Notas do Editor
Reproductive history and hormone exposureAge at menarche and menopauseUse of hormonal contraceptives and menopausal hormone therapiesNumber of births and miscarriagesAge at first birth and breastfeedingUse of natural and bioidentical hormones
The role for sun exposure as a risk factor for cancer risk came about since the proposal of the vitamin D hypothesis, some 30 years ago.It was proposed that Vtamin D deficiency can be a risk factor for various internal cancers namely breast and colon cancers. He based his evidence on ecological data showing increasing cancer risk with increasing latitude. Using latitude as a surrogate for UV, and solar UV exposure is the major source of our vitamin D production, he naturally attributed this effect to serum vitamin D levels.
The role of UV-induced immune suppression in skin cancer development is well documented.There is evidence showing induction of lymphoid malignancies, mainly in the spleen and liver, in genetically-modified mice exposed to solar-simulated UV suggesting thatUV-induced immune suppression might increase cancer risk at body sites distant from the site of UV exposure.While the evidence remains weak, there is also a possibility that prostate cancer is caused by an infectious agent, which might promote cancer development in the presence of UV-induced immune suppression, particularly when vitamin D activity is not increasing to counteract the effect of additional UV exposureAnd we therefore proposed Immune suppression as a possible mechanism whereby higher levels of solar UV exposure might increase prostate cancer risk.