Supporting Information
This document includes full details of methodological descriptions regarding data sources,
estimation of healthcare costs associated with hepatocellular carcinoma (HCC), 5-year net costs
of HCC care, and Supporting Tables S1-S3.
Data sources
The data source housed at the Institute for Clinical Evaluative Sciences (ICES) include a number
of linked health service utilization data for Ontario, Canada’s most populated province with
approximately 13 million people. The Ontario Cancer Registry (OCR) is a population-based
tumor registry of high quality,1,2 consisting of computerized information on all new cases of
cancer in Ontario (except non-melanoma skin cancers) since 1964.3 The registry is based on
multiple sources, probabilistically linked to compile incident cases of cancer in
Ontario.4_ENREF_44 The OCR includes information on age category (60 years and younger, 6170, 71-80, and 80 years or older), sex, birth location (Canada, Asia, Europe, Other, and missing),
cause of death, date of death, diagnosis date, postal code, and rurality (classified by whether or
not people were living in communities with less than 10,000 inhabitants).5
Using the perspective of the Ontario Ministry of Health and Long-Term Care, direct medical
costs were determined. Costs associated with outpatient physician visits and laboratory tests in
Ontario were determined from the Physician’s Claims History Database of the Ontario Health
Insurance Plan (OHIP), which includes fee-for-service claims submitted by providers for health
services provided to eligible Ontario residents. It also includes shadow billings from providers of
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organizations covered by alternate payment arrangements (i.e., non-fee-for-service physician
reimbursement). The Canadian Institute for Health Information (CIHI) Discharge Abstract
Database6 contains information pertaining to the “most responsible” diagnosis and up to 15
additional diagnosis codes that can be used to estimate comorbidity,7-9 as well as procedure
codes for all hospitalisations in Ontario, frequency and type of hospital admissions, length of
stay, and in-hospital mortality.10 Costs associated with radiofrequency ablation (RFA), surgical
resection, liver transplantation, transarterial chemoembolization (TACE), percutaneous ethanol
injection, chemotherapy, and sorafenib were determined using CIHI and OHIP databases.
International Statistical Classification of Diseases and Related Health Problems, 9th Revision
and 10th Revision (ICD-10) codes were used to identify diagnosis of liver failure or
potential complications of cirrhosis from the CIHI and OHIP databases (Supporting Table S2).
Costs for emergency room visits and same-day surgery were determined using the National
Ambulatory Care Reporting System (NACRS) Database,10 which contains administrative,
clinical, financial, and demographic data for hospital-based ambulatory care, including
emergency room visits, outpatient surgical procedures, medical day/night care, and high-cost
ambulatory clinics including outpatient oncology services.10
Medication costs were obtained from the Ontario Drug Benefit (ODB) Program Database,10
which contains comprehensive drug utilization information regarding prescription medications
(listed in the Ontario Drug Benefit Formulary) dispensed to Ontario residents as follows: those
aged 65 and above (seniors above an income threshold ($16,000 for individuals and $24,000 for
couples) pay the first $100 of medication costs and $6 per prescription thereafter); those under
65 receiving social assistance; receiving professional services under the Home Care Program;
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those eligible under the Trillium Drug Program—high drug costs relative to household
income;10_ENREF_8 and of Long-Term Care (LTC) facilities and Homes for Special Care.
Costs associated with home care, continuing care, and LTC, were determined using the Ontario
Home Care Database, Continuing Care Reporting System (CCRS), and ODB Program Database.
Home Care Database captures all services provided by or coordinated by Ontario’s Community
Care Access Centres, including visiting allied health care professionals (e.g., nurses,
physiotherapists), and personal, homemaking and community support. CCRS includes data on
medical LTC, geriatric assessment and rehabilitation, psychogeriatric care, palliative care, and
respite care for Ontario LTC residents since 1996 collected through the Resident Assessment
Instrument. The LTC reported in the CCRS only started in 2005 and is incomplete across
Ontario. For this reason, we used an algorithm applied on the LTC flag variable in the ODB to
determine periods a patient may have been residing in a LTC facility. The frequency of
hospitalization in the LTC was estimated from the Discharge Abstract Database.
Estimation of healthcare costs associated with HCC
The categories of costs included: all outpatient visits (including physicians’ and other fee-forservice practitioners’ services); emergency room visits; same-day surgery; acute inpatient care;
medications; home care; continuing care; and LTC. All costs were adjusted for inflation to 2010
Canadian dollars (CAD) using the Statistics Canada Consumer Price Index for health care and
personal items for Ontario.11 Purchasing Power Parity for Gross Domestic Product was used to
convert 2010 Canadian dollars to 2010 U.S. dollars.12 Because of regional variations in
reimbursements, the median 2008 cost for each physician and laboratory service fee code was
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used to estimate outpatient costs. The cost of hospitalization was estimated using the Resource
Intensity Weight (RIW) methodology developed by CIHI.10 Each case mix group (CMG) is
assigned a weight that represents the relative value of resources that cases within that CMG are
expected to consume when compared to other CMGs, and this value is called the RIW. CMGs
represent a Canadian patient classification system based on clinical information used to group
and describe types of inpatients discharged from acute care hospitals. A RIW is assigned to each
patient on discharge based on the CMG to which they are assigned and other factors, such as age
and comorbidities.10 We multiplied the yearly adjusted average provincial cost per weighted case
for all Ontario hospitals (ranging from U.S. $2,683 in 2001 to $4,935 in 2009), with the
corresponding year-specific RIW associated with the CMG for each hospitalization.10 This
method yielded a mean cost per hospitalization for cases assigned to a particular CMG. A
slightly different RIW methodology was employed to determine the costs for emergency room
visits (ranging from $3,528 in 2001 to $4,795 in 2009) and same-day surgery (ranging from
$2,683 in 2001 to $4,819 in 2009). In the NACRS Database, the 2008 RIW was used to estimate
costs for emergency room visits and same-day surgery since ICES had only derived the yearly
cost per weighted case based on the 2008 RIW. The unit costs for home care services (per hour,
2010 U.S. dollars) are summarized in the Supporting Table S3. The estimated costs of chronic
care per day in 2008 were $396.15. The Ministry of Health covers the costs associated with
nursing, food and programming for LTC residents ($79.50/day, 2001 U.S. dollars); patients are
responsible for accommodation costs ($40.53/day for ward). For people with more than one
OHIP fee, hospitalization, emergency room visit, or home care visit per day (all very few), we
combined the costs for all services in one day into a single visit. For people with more than one
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ODB script per day, we combined the costs for all drug prescriptions in one day into a single
drug cost.
5-year net costs of HCC care
We applied the incidence approach13,14 that involves using the mean net costs of HCC care by
phase, in conjunction with survival probabilities after HCC diagnosis accounting for competing
risks,15 to estimate 5-year net costs of care in diagnosed HCC patients. The probability of
survival, dying of HCC, dying of other causes, or any death was estimated using cancer registry
statistics from 2002 to 2008. Using the Kaplan–Meier method, we first calculated the overall
survival probability of being ‘event-free’ from the date of HCC diagnosis to either the date of
death as a result of HCC or the end of the study period. In the second step, we derived the
nonparametric estimates of the cumulative incidence function,15 which is the probability of
occurrence by time t for a particular type of event in the presence of other risks to yield the
probability of HCC death and non-HCC death at a specified month. The net costs at each 30-day
interval was then calculated by multiplying the mean net costs in the initial, continuing care and
terminal phases, by the proportions of patients surviving and dying of HCC or other cause of
death, or any death in each monthly interval. The cumulative 5-year net costs of HCC care were
the sum of the costs across all the three phases.14 The 5-year net cost of care for diagnosed HCC
patients was calculated using the formula based on Yabroff et al.14
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For patients dying in month i ( i = 1, …, 72) after diagnosis, let Initi , Conti , and Ti ( TC =
terminal, HCC death, and TO = terminal, other cause of death) denote the number of months
during the 5-year period that patients spent in the initial, continuing care, and terminal phases,
The lower and upper bound of the 95% CI for phase-specific net costs of care were used to
estimate a plausible range of 5-year net costs of care, which represents a conservative estimate of
the true 95% CI.14 Costs were discounted at 3% and 5% annually.
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Hall S, Schulze K, Groome P, Mackillop W, Holowaty E. Using cancer registry data for
survival studies: the example of the Ontario Cancer Registry. J Clin Epidemiol 2006;59:6776.
Marrett LD, Clarke EA, Hatcher J, Weir HK. Epidemiologic research using the Ontario
Cancer Registry. Can J Public Health 1986;77 Suppl 1:79-85.
Robles SC, Marrett LD, Clarke EA, Risch HA. An application of capture-recapture methods
to the estimation of completeness of cancer registration. J Clin Epidemiol 1988;41:495-501.
Clarke EA, Marrett LD, Kreiger N. Cancer registration in Ontario: a computer approach.
IARC Sci Publ 1991:246-257.
Statistics Canada Agriculture Division. Agriculture and Rural Working Paper Series
Working Paper No. 61. Definitions of “Rural”. Catalogue No. 21-601-MIE; December
2002. Available at: http://www.statcan.gc.ca/pub/21-601-m/21-601-m2002061-eng.htm.
Accessed Oct 13, 2011.
Canadian Institute for Health Information. Available at: http://www.cihi.ca. Accessed Oct
13, 2011.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic
comorbidity in longitudinal studies: development and validation. J Chronic Dis
Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD9-CM administrative databases. J Clin Epidemiol 1992;45:613-619.
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Jembere N, Campitelli MA, Sherman M, Feld JJ, Lou W, Peacock S, et al. Influence of
socioeconomic status on survival of hepatocellular carcinoma in the ontario population; a
population-based study, 1990-2009. PLoS One 2012;7:e40917.
10. Jacobs PYR. Using Canadian Administrative Databases to Derive Economic Data for Health
Technology Assessments. Ottawa: Canadian Agency for Drugs and Technologies in Health,
2009. Available at:
http://cadth.ca/media/pdf/H0483_Canadian_Admin_Databases_mg_e.pdf. Accessed June
19, 2011.
11. Statistics Canada. CANSIM Table 326-0021. Consumer Price Index (CPI), 2005 basket
content, annual (2002=100). Ottawa, ON, Canada: Statistics Canada, 2010. Available at:
http://www5.statcan.gc.ca/cansim/. Accessed Oct 4, 2011.
12. Organization for Economic Co-Operation and Development. Prices and Purchasing Power
Parities (PPP). 2012. Available at:
http://stats.oecd.org/Index.aspx?DatasetCode=SNA_TABLE4. Accessed Oct 22, 2012.
13. Hartunian NS, Smart CN, Thompson MS. The incidence and economic costs of cancer,
motor vehicle injuries, coronary heart disease, and stroke: a comparative analysis. Am J
Public Health 1980;70:1249-1260.
14. Yabroff KR, Lamont EB, Mariotto A, Warren JL, Topor M, Meekins A, et al. Cost of care
for elderly cancer patients in the United States. J Natl Cancer Inst 2008;100:630-641.
15. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York:
Wiley; 1980.
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Table S1. Selection criteria for hepatocellular carcinoma patient sample
Inclusion criteria
People with a valid Ontario health care number in the Ontario Cancer
Patient count
Registry (OCR) over the period 1990 to 2009 (ICES)
People diagnosed principally as primary liver cancer with International
Statistical Classification of Diseases and Related Health Problems, 9th
Revision (ICD-9) site code ‘155.0’ in the OCR over the period 1990-2009
People diagnosed principally as hepatocellular carcinoma (HCC) with
International Classification of Diseases for Oncology, Third Edition (ICDO-3) histology codes 8170-8175 in the OCR over the period 1990-2009
After excluding those who had death dates before or on diagnosis date
People diagnosed with HCC in the OCR over the study period 2002-2008
People diagnosed with HCC who did not have a second cancer during the
study period 2002-2008
No medical claims after date of death
HCC cases who were available to be matched to controls (non-HCC) in the
initial and continuing care phases
HCC cases matched to controls (non-HCC) for Cohort-1
HCC cases who were available to be matched to controls (non-HCC) in the
terminal phase (who died during the study period, 2002-2009)
HCC cases matched to controls (non-HCC) for Cohort-2
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Table S2. ICD-9 and ICD-10 codes to identify diagnosis of liver failure or potential
complications of cirrhosis*
ICD-9 code
ICD-10 code
Alcoholic cirrhosis of liver
571.5, 571.6
Cirrhosis of liver
Hepatic encephalopathy
Portal hypertension
Hepatorenal syndrome
Other sequelae of chronic liver disease
Esophageal varices with bleeding
Esophageal varices without mention of bleeding
Esophageal varices in diseases classified elsewhere
Alcoholic hepatic failure
Toxic liver disease with hepatic necrosis
Toxic liver disease with fibrosis and cirrhosis of liver
Hepatic failure, not elsewhere classified
Fibrosis and cirrhosis of liver
Hepatic veno-occlusive disease
Varicose veins of other sites
International Statistical Classification of Diseases and Related Health Problems, 9th Revision (ICD-9) and 10th
Revision (ICD-10) codes identified from the Canadian Institute for Health Information (CIHI) Discharge Abstract
Database and Ontario Health Insurance Plan (OHIP) databases.
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Table S3. Unit costs (2010 U.S. dollars) for health services per hour in Ontario
Home Care Database
Case management
Homemaking service
Personal service
Combined personal and homemaking services
Nursing shift
Nursing visit
Occupational therapy
Respiratory technology service
Respite service
Social work
Speech/language therapy
Placement service (0.03%)
Missing home care service type information (0.013%)
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Unit cost $
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