Colorectal cancer risk according to family history
Background[edit source]
The best evidence for the association between colorectal cancer risk and family history of the disease comes from cohort studies that compare the risk of colorectal cancer for people with and without a family history of colorectal cancer. Ideally, these studies should take into account any differences between people with and without a family history for colorectal cancer risk factors.
Such studies consistently report an elevated risk of colorectal cancer associated with family history. The strength of this association increases with the number of relatives with colorectal cancer, the closeness of genetic relationship of the relative(s) with colorectal cancer, and the diagnosis age of relative(s) diagnosed with colorectal cancer.
Case control studies and cohort studies which have been well designed including stringent methods for collection of family cancer data in relatives, reported an approximate doubling of lifetime risk.[1][2][3][4] For example:
- A Danish study of parents of colorectal cancer patients diagnosed before age 60 years[1] reported that, compared with the average population, the risk of colorectal cancer was 1.6 times higher among patients’ mothers and 1.9 times higher among patients’ fathers.
- An Australian study reported that, compared to people with no relative with colorectal cancer, those with one relative with colorectal cancer had 1.8 times the colorectal cancer risk.[2]
- A US study of people reported that the risk of colorectal cancer for men and women of first-degree relatives with colorectal cancer was 1.72 greater than for those without a family history of the disease[3]
- A US study reported that the risk of colon cancer was 2.2 times higher among patients with a first-, second- or third-degree relative with colon cancer than for those with no family history.[4]
In contrast to these modest levels of increased risk, colorectal cancer risk has been found to be substantially (three- to six-fold) greater for those who have a first-degree relative with colorectal cancer diagnosed at an early age (below age 55) or when two close relatives have had colorectal cancer, irrespective of the age at diagnosis.[3][4][3]
For information on risk associated with specific high-risk familial syndromes, see High-risk familial syndromes.
Update of systematic review evidence[edit source]
For individuals, has a family history of colorectal cancer been shown to be reliably associated with an increase in risk of occurrence of or death from colorectal cancer when compared to individuals who do not have a family history of colorectal cancer? (FHS2)
A systematic review of cohort studies since 2005 (the publication of the previous guidelines[5]) was undertaken to update the evidence for the estimated risk of colorectal cancer for relatives of patients with colorectal cancer. Cohort studies are less subject to recall misclassification than case-control studies in which people with colorectal cancer more likely to report any existing family history than controls.
The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Six studies were identified: one analysis of pooled data from two prospective cohort studies,[6] and five cohort studies[7][8][9][10][11]. All measured colorectal cancer outcomes (diagnosis or mortality) for people without a colorectal cancer diagnosis (or symptoms that might indicate colorectal cancer) at time of recruitment, and assessed risk according to the individual’s independently confirmed family history of colorectal cancer. An additional modelling study[12] was also identified.
Of the cohort studies, one[9] was deemed to have a low risk of producing biased estimates, two[7][11] were deemed to have a moderate risk of bias, and three[6][8][10] were deemed to have a high risk of bias.
Increased risk of colorectal cancer by family history[edit source]
Overall, cohort studies report that people with a family member diagnosed with colorectal cancer have an increased risk of colorectal cancer, compared with the average population. Estimated increases in risk depend on the age at which the family member was diagnosed, and the number of first-degree and second-degree relatives with colorectal cancer (Table 5.1).
Individual colorectal cancer risk (personal risk) could, in theory, be estimated based on a person’s specific family history and personal screening recommendations could be devised based on this increased risk. However, for practical reasons, only three categories of risk have been developed (Table 5.1), each with screening recommendations based on the average risk for that category.
Table 5.1. Increased risk of colorectal cancer based on family history: results from cohort studies published since 2005[edit source]
| Family history of colorectal cancer | Colorectal cancer risk relative to the average population risk |
|---|---|
| No family history | 0.86[11]
(14% decrease) |
| One or more first-degree relative diagnosed at any age | 1.4[10] – 2.1[8], 2.05[11]
(40–110% increase) |
| One first-degree relative diagnosed before age 50 | 3.3[11]
(230% increase) |
| One first-degree relative diagnosed between ages 50 and 60 | 2.2[10] to 2.5[11]
(120–150% increase) |
| Two or more first-degree relatives | 3.0[11]
(200% increase) |
| No first-degree relative, at least one second-degree relative | 1.1-1.5[11]
(10–50% increase) |
Category 1 — those near average risk[edit source]
Lifetime risk is to age 75 years: approximately 5% to 10% (assuming no colorectal cancer screening).
Some examples of asymptomatic people who fit into this category are the following (for a full description see Table 5.3 below):[2][4][3][6][8][10][12][13]:
- no first- or second-degree relative with colorectal cancer
- one first-degree or one first and one second-degree relative with colorectal cancer diagnosed at age 55 years or older.
For those with an affected first-degree relative, risk is double the average risk, although most of that extra risk is expressed after the age of 60 years. When the affected relative is second-degree (e.g. a grandparent, uncle or aunt), lifetime risk is only up to 1.5 times higher than average.[4][11]
Category 2 — those at moderately increased risk[edit source]
Lifetime risk to age 75 years: approximately 15–30% (assuming no colorectal cancer screening).
Some examples of asymptomatic people who fit into this category if they have none of the high-risk features listed in category 3 and have either of the following (for a full description see Table 5.3 below):
- one first-degree relative with colorectal cancer diagnosed before the age of 55 years[2][4][11][14][15][16]
- two first-degree relatives or one first-degree relative and at least two second-degree relative diagnosed with colorectal cancer at any age.[11][15][16][17]^
Relative risk in these two situations is increased to 3–6 times average risk. For the majority of people in this category, the risk of colorectal cancer is 3–4 times higher than average.
^Note: Previous guidelines specified that relatives with cancer needed to be on the same side of the family in order to meet eligibility of this risk category. Recent data suggests that a similar level of risk occurs if the relatives with cancer are on opposite sides of the family,[11] therefore this restriction has now been omitted.
Category 3 — those at high risk[edit source]
Lifetime risk to age 75: approximately 30–40% (assuming no colorectal cancer screening).
Asymptomatic people fit into this category if they have any of the following:
- at least three first-degree relatives diagnosed with colorectal cancer at any age[11]
- at least three first-degree or second-degree relative with colorectal cancer with at least one diagnosed before age 55 years.^
Relative risk for category 3 is 7–10 times average risk. For the majority of people in this category, the risk of colorectal cancer is 7 times higher than average.
^Note: Previous guidelines specified that relatives with cancer needed to be on the same side of the family in order to meet eligibility of this risk category. Recent data suggests that a similar level of risk occurs if the relatives with cancer are on opposite sides of the family,[11] therefore this restriction has now been omitted.
Category 2 and 3 excludes people known to be, or have a high probability of having a high-risk familial syndrome due a genetic predisposition to colorectal cancer. These people have potentially a much higher risk of colorectal cancer and therefore more intensive screening is recommended. See High-risk familial syndromes.
Therefore these categories excludes people who have:
- a relative confirmed as carrying a pathogenic mutation in a gene associated with a high-risk familial syndrome, who have not themselves been tested
- a relative with multiple colorectal cancers
- a relative with familial adenomatous polyposis
- at least three first-degree or second-degree relatives with a Lynch syndrome-related cancer (endometrial, ovarian, stomach, small bowel, renal pelvis or ureter, biliary tract, brain) with at least one diagnosed before age 55 years).
For guidance on managing risk in people in category 3 with a known or suspected genetic syndrome, see High-risk familial syndromes.
Table 5.2. Relative risk of colorectal cancer based on family history[edit source]
| Category | Examples of Family history (full description in Table 5.3) | Risk compared with the average population. |
|---|---|---|
| 1 | No first- or second-degree relative with colorectal cancer | 10% decreased risk |
| One first-degree relative with colorectal cancer diagnosed at 55 years or older
One first-degree and one second-degree with colorectal cancer diagnosed at 55 years or older |
Up to 2-fold increased risk | |
| 2 | One first-degree relative with colorectal cancer diagnosed under 55 years
Two first-degree relatives with colorectal cancer diagnosed at 55 years or older One first-degree relative and at least two second-degree relative with colorectal cancer diagnosed at 55 years or older |
3- to 6-fold increased risk |
| 3 | At least three first-degree or second-degree relatives with colorectal cancer, with at least one diagnosed under 55 years
At least three first-degree relatives with colorectal cancer diagnosed at 55 years or older |
7- to 10-fold increased risk |
Sources: St John et al (1993)[2], Fuchs et al (1994)[3], Slattery et al (1994)[4], Bass et al (2008)[7], Schoen et al (2015)[9], Taylor et al (2011)[11], Lynch et al (2003)[13], Hall et al (1996)[14], Leu et al (2008)[12], Benhamiche-Bouvier et al (2000)[15], Sandhu et al (2001)[16], Aitken et al (1996)[17], Anderson et al (2003)[18]
Note: Relative risk is the ratio of the risk of developing colorectal cancer in a particular exposed group to the average risk in the whole population.
Table 5.3. Colorectal cancer risk categories by family history[edit source]
|
Risk category by family history |
Number of 1st degree relatives with CRC before age 55
| |||||||||||
| 0 | 1 | 2 | ||||||||||
Number of 1st degree relatives with CRC at 55 or older
| ||||||||||||
| 0 | 1 | 2 | 3 | 0 | 1 | 2 | 0 | 1 | ||||
Number of 2nd degree relatives with CRC before age 55
|
0 | Number of 2nd degree relatives with CRC at 55 or older
|
0 | 1 | 1 | 2 | 3 | 2 | 2 | 3 | 3 | 3 |
| 1 | 1 | 1 | 2 | 3 | 2 | 3 | 3 | 3 | 3 | |||
| 2 | 1 | 2 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | |||
| 3 | 2 | 2 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | |||
| 4 | 2 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | |||
| 1 | 0 | 1 | 2 | 3 | 3 | 2 | 3 | 3 | 3 | 3 | ||
| 1 | 2 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | |||
| 2 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | |||
| 2 | 0 | 2 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | ||
| 1 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | 3 | |||
Evidence summary and recommendations[edit source]
| Evidence summary | Level | References |
|---|---|---|
| Category 1 – Those near average risk
Approximately 95–98% of the population are in this category. Those with a weak family history, which is approximately 65% of those with any family history, will also be in this category. For the majority of people, the risk of colorectal cancer ranges from slightly below average to slightly above average. For some people, risk will be increased up to two-fold the average risk. Approximately 10% of people in this group will develop colorectal cancer in their lifetime. |
II, III-2 | [17], [18], [19], [20], [21], [22], [23], [24] |
| Category 2 – Those at moderately increase risk
Approximately 2–5% of the population are in this category. The risk of colorectal cancer is approximately three- to six-fold higher than average. Approximately 15–30% of people in this group will develop colorectal cancer in their lifetime. |
II, III-2 | [2], [4], [14], [15], [16], [17] |
| Category 3 – Those at potentially high risk
Less than 1% of the population are in this category. The risk of colorectal cancer is approximately seven to ten-fold higher than average. Approximately 30–40% of people in this group will develop colorectal cancer in their lifetime. |
II, III-2 | [25], [26], [27], [28] |
Important note: These recommendations are in relation to the risk of colorectal cancer for relatives of patients with colorectal cancer. For recommendations about tailored screening categories 1-3, please see Screening strategies for people with a family history of colorectal cancer.
Evidence-based recommendation
|
Grade |
|---|---|
 People who have one relative with colorectal cancer diagnosed at age 55 or older should be advised that their own risk of developing colorectal cancer could be up to twice the average risk, but is still not high enough to justify CRC screening by colonoscopy. |
C |
| Evidence-based recommendation
|
Grade |
|---|---|
People should be advised that their risk of developing colorectal cancer is at least three times higher than average, but could be up to six times higher than average, if they have any of the following:
|
C |
| Evidence-based recommendation
|
Grade |
|---|---|
People should be advised that their risk of colorectal cancer is at least seven times higher than average, but could be up to 10 times higher than average, if they have either of the following:
|
C |
| Practice point
|
|---|
|
Approximately 95-98% of the population are in Category 1 (near average risk of developing colorectal cancer). |
| Practice point
|
|---|
|
Approximately 65% of those with a family history of colorectal cancer only have a weak family history which means they are category 1 risk. |
| Practice point
|
|---|
|
Medical information that patients provide about their relatives is often inaccurate. (St John et al 1993, Love et al 1985, Douglas et al 1999, Ruo et al 2001, Mitchell et al 2004) The percentage of colorectal cancer reports that are correct (positive predictive value) is 86% meaning that reports by relatives are usually true. However, a high proportion of people appear to be unaware that their relatives have had colorectal cancer, with the percentage of all colorectal cancers in first-degree relatives that are reported (sensitivity) being 27%. (Mai 2011). |
| Practice point
|
|---|
|
Given the potential importance of an accurate risk prediction for an individual, every effort should be made to collect reliable information. |
| Practice point
|
|---|
|
When there is uncertainty on family history, people should be encouraged to seek clarification within their family including details on which relatives have had colorectal cancer and their ages of diagnoses. |
| Practice point
|
|---|
|
If a family medical history appears to be significant but diagnoses prove difficult to confirm, it may be appropriate to seek expert help from a familial cancer clinic who have resources available to confirm cancer diagnoses. |
Considerations in making these recommendations[edit source]
There was robust discussion by the Working Party about the categories of risk outlined in this chapter. For category 3, there was discussion regarding the decision to exclude people known to have, or with a high probability of having, a high-risk familial syndrome due to a genetic predisposition to colorectal cancer. Ultimately the Working Party was in agreement about the three-level risk categorisation and feel this is adequately outlined in the chapter.
Health system implications[edit source]
Clinical practice[edit source]
The RACGP recommended use of validated family history screening questionnaire to identify people in general practice with significant family history of cancer.[29]
Under-ascertainment of people with a significant family history to general practice requires the need for more proactive approaches in primary care to identify families at increased risk of CRC.
Resourcing[edit source]
There are no known resourcing implications.
Barriers to implementation[edit source]
Current GP software systems do not support systematic family history collection or risk assessment here.
Discussion[edit source]
Unresolved issues[edit source]
The effect of a family history of adenoma on colorectal cancer risk is unknown, although increased risk is likely. There is insufficient evidence from which to determine the effect of family history of adenomas or advanced adenomas on colorectal cancer risk.
Because of the increasing uptake of colonoscopy in the population and the removal of pre-malignancies, recent studies of family history as a risk factor may be underestimating the true association of colorectal cancer risk with family history of the disease. Therefore older studies may be more relevant to estimates of familial risk.
Studies currently underway[edit source]
We are not aware of any current trials that would provide more data on this question.
Future research priorities[edit source]
Inherent difficulties in deciding the demarcation between categories or the number of categories argues for an algorithm that summarises the family history of colorectal cancer into a risk score that can then be used to decide age and modality of screening. These algorithms should also assess the effect on the accuracy of risk stratification of including personal risk factors for colorectal cancer other than family history.
Identifying the causes for familial risk of colorectal cancer will assist the evaluation of risk within these risk categories, so that more personalised screening can be recommended based on more precise estimates of risk.
Next section: screening strategies for people with a family history of colorectal cancer
References[edit source]
- ↑ 1.0 1.1 Søndergaard JO, Bülow S, Lynge E. Cancer incidence among parents of patients with colorectal cancer. Int J Cancer 1991 Jan 21;47(2):202-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1988364.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 St John DJ, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ES. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993 May 15;118(10):785-90 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8470852.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer. N Engl J Med 1994 Dec 22;331(25):1669-74 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7969357.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Slattery ML, Kerber RA. Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 1994 Nov 2;86(21):1618-26 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7932826.
- ↑ Australian Cancer Network Colorectal Cancer Guidelines Revision Committee. Clinical practice guidelines for the prevention, early detection and management of colorectal cancer. The Cancer Council Australia and Australian Cancer Network 2005.
- ↑ 6.0 6.1 6.2 Wei EK, Giovannucci E, Wu K, Rosner B, Fuchs CS, Willett WC, et al. Comparison of risk factors for colon and rectal cancer. Int J Cancer 2004 Jan 20;108(3):433-42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14648711.
- ↑ 7.0 7.1 7.2 Bass AJ, Meyerhardt JA, Chan JA, Giovannucci EL, Fuchs CS. Family history and survival after colorectal cancer diagnosis. Cancer 2008 Mar 15;112(6):1222-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18219663.
- ↑ 8.0 8.1 8.2 8.3 Murphy G, Shu XO, Gao YT, Ji BT, Cook MB, Yang G, et al. Family cancer history affecting risk of colorectal cancer in a prospective cohort of Chinese women. Cancer Causes Control 2009 Oct;20(8):1517-21 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19418234.
- ↑ 9.0 9.1 9.2 Schoen RE, Razzak A, Yu KJ, Berndt SI, Firl K, Riley TL, et al. Incidence and mortality of colorectal cancer in individuals with a family history of colorectal cancer. Gastroenterology 2015 Nov;149(6):1438-1445.e1 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26255045.
- ↑ 10.0 10.1 10.2 10.3 10.4 Stefansson T, Moller PH, Sigurdsson F, Steingrimsson E, Eldon BJ. Familial risk of colon and rectal cancer in Iceland: evidence for different etiologic factors? Int J Cancer 2006 Jul 15;119(2):304-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16477631.
- ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 Taylor DP, Stoddard GJ, Burt RW, Williams MS, Mitchell JA, Haug PJ, et al. How well does family history predict who will get colorectal cancer? Implications for cancer screening and counseling. Genet Med 2011 May;13(5):385-91 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21270638.
- ↑ 12.0 12.1 12.2 Leu M, Reilly M, Czene K. Evaluation of bias in familial risk estimates: a study of common cancers using Swedish population-based registers. J Natl Cancer Inst 2008 Sep 17;100(18):1318-25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18780865.
- ↑ 13.0 13.1 Lynch KL, Ahnen DJ, Byers T, Weiss DG, Lieberman DA. First-degree relatives of patients with advanced colorectal adenomas have an increased prevalence of colorectal cancer. Clin Gastroenterol Hepatol 2003 Mar;1(2):96-102 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15017501.
- ↑ 14.0 14.1 14.2 Hall NR, Bishop DT, Stephenson BM, Finan PJ. Hereditary susceptibility to colorectal cancer. Relatives of early onset cases are particularly at risk. Dis Colon Rectum 1996 Jul;39(7):739-43 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8674364.
- ↑ 15.0 15.1 15.2 15.3 Benhamiche-Bouvier AM, Lejeune C, Jouve JL, Manfredi S, Bonithon-Kopp C, Faivre J. Family history and risk of colorectal cancer: implications for screening programmes. J Med Screen 2000;7(3):136-40 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11126162.
- ↑ 16.0 16.1 16.2 16.3 Sandhu MS, Luben R, Khaw KT. Prevalence and family history of colorectal cancer: implications for screening. J Med Screen 2001;8(2):69-72 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11480446.
- ↑ 17.0 17.1 17.2 17.3 Aitken JF, Bain CJ, Ward M, Siskind V, MacLennan R. Risk of colorectal adenomas in patients with a family history of colorectal cancer: some implications for screening programmes. Gut 1996 Jul;39(1):105-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8881819.
- ↑ 18.0 18.1 Anderson JC, Attam R, Alpern Z, Messina CR, Hubbard P, Grimson R, et al. Prevalence of colorectal neoplasia in smokers. Am J Gastroenterol 2003 Dec;98(12):2777-83 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14687832.
- ↑ Pedersen A, Johansen C, Grønbaek M. Relations between amount and type of alcohol and colon and rectal cancer in a Danish population based cohort study. Gut 2003 Jun;52(6):861-7 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12740343.
- ↑ Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003 Apr 24;348(17):1625-38 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12711737.
- ↑ Grossman S, Milos ML. Colonoscopic screening of persons with suspected risk factors for colon cancer. I. Family history. Gastroenterology 1988 Feb;94(2):395-400 Available from: http://www.ncbi.nlm.nih.gov/pubmed/3335314.
- ↑ Luchtefeld MA, Syverson D, Solfelt M, MacKeigan JM, Krystosek R, Waller J, et al. Is colonoscopic screening appropriate in asymptomatic patients with family history of colon cancer? Dis Colon Rectum 1991 Sep;34(9):763-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1914741.
- ↑ Rex DK, Lehman GA, Ulbright TM, Smith JJ, Pound DC, Hawes RH, et al. Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am J Gastroenterol 1993 Jun;88(6):825-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8503374.
- ↑ Hunt LM, Rooney PS, Hardcastle JD, Armitage NC. Endoscopic screening of relatives of patients with colorectal cancer. Gut 1998 Jan;42(1):71-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9505888.
- ↑ Rhodes M, Bradburn DM. Overview of screening and management of familial adenomatous polyposis. Gut 1992 Jan;33(1):125-31 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1310949.
- ↑ Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 1996 Sep 15;78(6):1149-67 Available from: http://www.ncbi.nlm.nih.gov/pubmed/8826936.
- ↑ Järvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut 1992 Mar;33(3):357-60 Available from: http://www.ncbi.nlm.nih.gov/pubmed/1314763.
- ↑ Järvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995 May;108(5):1405-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7729632.
- ↑ Emery JD, Reid G, Prevost AT, Ravine D, Walter FM. Development and validation of a family history screening questionnaire in Australian primary care. Ann Fam Med 2014 May;12(3):241-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24821895.
Appendices[edit source]
