Methods

Table A    Data on incidence, relative risk, mortality, and quality of life used in model, with references

Table B    Distributions used to model data on incidence, mortality, and quality of life used in model.
 

Methods

Data and assumptions

Table A shows the source for all data used in the model, and table B shows the distribution used to model the uncertainty around each point estimate.

Data on incidence and mortality

For all outcomes:

• Data refer to the target population (white UK 50 year old women) over a five year period, with the exceptions reported in the footnotes of table A.

• The standard deviation (SD) for the annual incidence was calculated as:

SD=sqrt[C]/Y

where C is the number of cases and Y is person years.

• The cumulative incidence over a period of five years was calculated by multiplying the incidence rate by 5, assuming that the incidence rate was constant over that period.

The standard deviation (SD) for the cumulative incidence (CMI) was calculated from the SD of the incidence rate (IR):

VAR(CMI)=5²*VAR(IR), so that: SD(CMI)=5*SD(IR)

Data on cumulative incidence were modelled using a gamma distribution, where the parameters were calculated using the "method of moments" based on the mean and variance.

• For information on cause specific deaths, when only relative survival data were available, the percentage of cause specific deaths over five years was calculated based on five year relative survival: % cause specific deaths=1- relative survival.

The standard deviation (SD) for the cause specific deaths was calculated as:

SD=sqrt[P(1- P)/N]

where P is the proportion of deaths and N is the number of patients affected by the disease.

Data on mortality were modelled using a beta distribution, where the parameters were calculated using the "method of moments" based on the mean and variance.

Data on relative risk

• Data from women’s health initiative trial: results were reported as "hazard ratio," which we have taken as an approximation of the relative risk.
• Data from HERS I and II trial: results were reported as "relative hazard," which we have taken as an approximation of the relative risk.
• From EVTET trial: the relative risk was calculated from the raw data.
• Data from Cochrane Review on the effect of hormone replacement therapy (HRT) for hot flushes: The relative risk has been calculated from the raw data reported for the subgroup of women treated with combined HRT (in the original paper "presence versus absence of hot flushes"; comparison 04, outcome 06).
• In the model the pooled log relative risks were assumed to be normally distributed.

Data on quality of life

• Data referring to the target population (allowing an age between 45 and 65) were selected when obtained on unaffected women in the community by a time trade-off method. Exceptions are reported in the footnotes of table A.

• Being characteristically bounded between 0 and 1, all quality of life data were modelled using beta rather than normal distributions, where the parameters were estimated using the "method of moments" based on the mean and variance.
• The variance was calculated from the standard error (SE) of the mean, which was either directly reported in the original papers or calculated from the 95% confidence interval (95% CI) or interquartile range. The 95% CIs reported in table A were calculated from the SE of the quality of life weight.

1. Lau EM, Cooper C, Wickham C, Donnan S, Barker DJ. Hip fracture in Hong Kong and Britain. Int J Epidemiol 1990;19:1119-21.
2. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66.
3. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
4. Keene GS, Parker MJ, Pryor GA. Mortality and morbidity after hip fractures. BMJ 1993;307:1248-50.
5. Tosteson AN, Gabriel SE, Grove MR, Moncur MM, Kneeland TS, Melton LJ 3rd. Impact of hip and vertebral fractures on quality-adjusted life years. Osteoporos Int 2001;12:1042-9.
6. MacLennan A, Lester S, Moore V. Oral oestrogen replacement therapy versus placebo for hot flushes. Cochrane Database of Systematic Reviews. Issue 3, 2002. Date of most recent substantive update 19 Sept 2000.
7. Daly E, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ 1993;307:836-40.
8. Office for National Statistics. Cancer trends in England and Wales 1950-1999. Studies on medical and population subjects No 66. www.statistics.gov.uk (accessed 19 Dec 2003).
9. Office for National Statistics. Cancer survival trends in England and Wales, 1971-1995: deprivation and NHS region. www.statistics.gov.uk (accessed 19 Dec 2003).
10. Dominitz JA, Provenzale D. Patient preferences and quality of life associated with colorectal cancer screening. Am J Gastroenterol 1997;92:2171-8.
11. Hillner BE, Hollenberg JP, Pauker SG. Postmenopausal estrogens in prevention of osteoporosis. Benefit virtually without risk if cardiovascular effects are considered. Am J Med 1986;80:1115-27.
12. Grann VR, Panageas KS, Whang W, Antman KH, Neugut AI. Decision analysis of prophylactic mastectomy and oophorectomy in BRCA1-positive or BRCA2-positive patients. J Clin Oncol 1998;16:979-85.
13. Hu FB, Stampfer MJ, Manson JE, Grodstein F, Colditz GA, Speizer FE, et al. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. N Engl J Med 2000;343:530-7.
14. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
15. Rosamond WD, Chambless LE, Folsom AR, Cooper LS, Conwill DE, Clegg L, et al. Trends in the incidence of myocardial infarction and in mortality due to coronary heart disease, 1987 to 1994. N Engl J Med 1998;339:861-7.
16. Fryback DG, Dasbach EJ, Klein R, Klein BE, Dorn N, Peterson K, et al. The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors. Med Decis Making 1993;13:89-102.
17. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.
18. Hoibraaten E, Qvigstad E, Arnesen H, Larsen S, Wickstrom E, Sandset PM. Increased risk of recurrent venous thromboembolism during hormone replacement therapy—results of the randomized, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET). Thromb Haemost 2000;84:961-7.
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Table A    Data on incidence, relative risk, mortality, and quality of life used in model, with references
 

Outcome	Annual incidence (SD)	5 year cumulative incidence (SD)	Relative risk in 5 years (95% CI)	Pooled relative risk (95% CrI)	5 year cause specific mortality (SD)	Quality of life weight (95% CI)
Benefit:
Hip fracture	0.0001761 (0.000088)	0.000880 (0.000441)	HERS I and II21.61 (0.98 to 2.66); WHI30.66 (0.45 to 0.98)	0.94 (0.68 to 1.25)	0.1584 b,c (0.059169)	0.925 c,d (0.82 to 0.99)
Menopausal    symptoms	—e	—e	—	Cochrane Review6 0.28 (0.18 to 0.44)	—f	0.757 g (0.66 to 0.83)
Colorectal cancer	0.0003698 (0.000009)	0.001845 (0.000045)	HERS I and II2 0.81 (0.46 to 1.45); WHI3 0.63 (0.43 to 0.92)	0.69 (0.49 to 0.96)	0.5569 (0.006534)	0.8010 b,c,d (0.74 to 0.86)
Endometrial cancer	0.0002458 (0.000007)	0.001225 (0.000037)	HERS I and II2 0.25 (0.05 to 1.18); WHI3 0.83 (0.47 to 1.47)	0.75 (0.42 to 1.24)	0.1709 (0.005995)	0.9011 h (0.70 to 0.98)
Harm:
Breast cancer	0.0024528 (0.000023)	0.012260 i (0.000116)	HERS I and II2 1.27 (0.84 to 1.94); WHI3 1.26 (1.00 to 1.59)	1.27 (1.03 to 1.55)	0.3009 (0.002987)		0.89 12 (0.86 to 0.92)
Coronary heart disease	0.00053013 l (0.000136)	0.002650 (0.000680)	HERS I and II14 0.99 (0.84 to 1.17); WHI3 1.29 (1.02 to 1.63)	1.08 (0.94 to 1.24)	0.23015 c,l (0.007717)		0.8616 b,c (0.85 to 0.88)
Pulmonary embolism	0.00058017 l (0.000219)	0.002900 (0.001096)	HERS I and II2 2.86 (1.13 to 7.26); EVTET18 2.92 (0.31 to 27.35); WHI3 2.13 (1.39 to 3.25)	2.31 (1.54 to 3.31)	0.08519 b,c,l,m (0.005630)		0.8720 b (0.84 to 0.91)
Stroke	0.00081321 b (0.000230)	0.004064 (0.001149)	HERS I and II2 1.09 (0.88 to 1.35); WHI3 1.41 (1.07 to 1.85)	1.21 (1.02 to 1.42)	0.36721 b,c,n,o (0.013611)		0.8616 b,c (0.85 to 0.87)

CrI=credibility interval (analogous to confidence interval); WHI=women’s health initiative trial; HERS=heart and estrogen/progestin replacement study; EVTET=estrogen in venous thromboembolism trial.

^aHormone replacement therapy versus no hormone replacement therapy.

^bIncludes men.

^cIncludes wide age group.

^d Includes hospital outpatients without the condition.

^eModel assumes either a purely asymptomatic or a purely symptomatic population.

^fNo mortality associated with menopausal symptoms.

^gWomen with and without menopausal symptoms (affected and unaffected women in the community, respectively); 0.75 is average quality of life weight across groups.

^hBased on expert opinion.

ⁱValue not used in model as net benefit was calculated for different fixed average levels of breast cancer risk.

^lUS data.

^mMortality within first three months; considered equivalent to five year cause specific mortality as increases were small after this time.

ⁿIncludes women of other ethnic groups.

^oMortality within first six months; considered equivalent to five year cause specific mortality as increases were small after this time.
 
 

Table B    Distributions used to model data on incidence, mortality, and quality of life used in model.
 

Outcome	Distributions
	Gamma for cumulative incidence over 5 years		Beta for cause specific deaths			Beta for quality of life weight
Benefit:
Hip fracture	Gamma (5029, 4.43)		Beta (5.8, 31)			Beta (28, 2.5)
Menopausal symptoms	—*		—†			Beta (73, 25)
Colorectal cancer	Gamma (92 2500, 1702)		Beta (3214, 2566)			Beta (147, 37)
Endometrial cancer	Gamma (12 25 000, 1501)		Beta (668, 3261)			Beta (15, 1.7)
Harm:
Breast cancer	—‡		Beta (7078, 16516)			Beta (402, 50)
Coronary heart disease	Gamma (5300, 14.05)		Beta (687, 2291)			Beta (1300, 205)
Pulmonary embolism	Gamma (2417, 7.01)		Beta (208, 2243)			Beta (308, 46)
Stroke	Gamma (3126, 12.7)		Beta (460, 793)			Beta (1840, 300)

*Model assumes either a purely asymptomatic or a purely symptomatic population.

†No mortality associated with menopausal symptoms.

‡Cumulative incidence not used in model as net benefit was calculated for different fixed average levels of breast cancer risk.