a decision analytic model ( figure 1 ) was developed to compare the lifetime costs and effects of genetically screening all uk aj women age 30 years and older for brca fm , compared with the current practice of screening using fh - based criteria ( 10% mutation risk ) ( supplementary table 1 , available online ) .
the model assumes that all women in the population screening arm and only those with a strong fh in the fh arm are offered genetic counseling and genetic testing
. a 71% uptake rate of genetic testing ( estimated from the gcapps study ) was incorporated into the model .
genetic testing involved analysis for the three brca fm associated with jewish descent in a national health service ( nhs ) genetics laboratory . in line with current guidelines ( 18,19 ) women testing positive were offered risk - reducing salpingo - oophorectomy ( rrso ) to reduce their ovarian cancer risk ( 20,21 ) and mri / mammography screening or risk - reducing mastectomy ( rrm ) ( 22 ) to reduce their breast cancer risk .
use of a selective estrogen receptor modulator ( serm ) for breast cancer chemoprevention ( 23 ) was also included in the model as part of a sensitivity analysis , but ovarian cancer screening was excluded , as its clinical value remains uncertain ( 24 ) . in line with guidelines on the reference case for economic evaluation from the national institute of health and clinical excellence ( nice ) , all costs and outcomes were discounted at 3.5% ( 25 ) .
the upper part of the model structure reflects a population - based approach to brca testing , and the lower part of the model depicts a family history ( fh)based approach .
node ,  and each path extending from a node is called a decision  branch . 
each decision is given a probability ( probabilities p1 to p14 used in the model are explained in table 1 ) highlighted in a white box along the decision branch .
cancer incidence was estimated by summing the probabilities of pathways ending in ovarian or breast cancer .
final outcomes ( blue boxes on the right of the figure ) of each path include development of breast cancer ( bc ) , ovarian cancer ( oc ) and no breast / ovarian cancer ( no oc or bc ) .
bc = breast cancer ; no oc or bc = no ovarian cancer or breast cancer developed ; oc = ovarian cancer ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
all pathway probabilities for the model are presented and explained in table 1 . a one - way sensitivity analysis involved rerunning the model at both lower and upper values / limits of the 95% confidence interval or range of all probability parameters ( table 1 ) used in the model ( figures 2 and 3 ) .
cancer incidence was estimated by summing the probabilities of pathways ending in ovarian or breast cancer
the total population impact was estimated by multiplying the results per woman by 81224 ( 0.71 * 114400 ) .
probabilities of different pathways in the model * * ci = confidence interval ; fh = family history ; fm = founder mutations ; gcapps = genetic cancer prediction through population screening study ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
p1 : the probability of carrying a brca fm in the aj population ( p1 = 0.0245 ) is taken from the gcapps study , as it provides uk - based data and is consistent with reports from other countries ( 2,86 ) .
p2 : the probability that brca1/2 carrier will undergo rrm is taken from an analysis of uk brca1/2 carriers by evans et al .
2009 . a composite uptake rate ( p2 = 0.52 ) for brca1 ( 60% rrm rate ) and brca2 ( 43% rrm rate ) carriers weighted for the relative prevalence of brca1 and brca2 fm found in the london aj population was computed ( 71 ) .
p3 : the reduction in ovarian cancer risk obtained from rrso ( p3 = 0.96 ) is taken from previous studies , which report a 4% residual risk of primary peritoneal cancer following rrso ( 20 ) .
p4 : a wide range of ovarian cancer risks have been reported for brca carriers , with higher penetrance estimates found in carriers ascertained from high - risk families with multiple cancer cases ( 87 ) .
our analysis uses ovarian cancer penetrance figures ( 40% for brca1 , 18% for brca2 ) from a meta - analysis , corrected for ascertainment ( 61 ) . to simplify the analysis , we have used a composite risk for brca1 and brca2 carriers ( p4 = 0.2987 ) , weighted for the relative prevalence of brca1 and brca2 fm found in the london aj population . the brca1 population prevalence is 0.0132 , and brca2 population prevalence is 0.0113 ( gcapps study )
. the overall risk of ovarian cancer in brca carriers is calculated as ( ( 0.0132 * 0.4)/2.45 + ( 0.0113 * 0.18)/2.45 ) .
p5 : the risk of ovarian cancer in a low - risk population ( p5 = 0.0185 ) is obtained from cancer research uk ( 84 ) .
p6 : the probability of having a strong fh of cancer fulfilling the current clinical criteria ( fh - positive ) is obtained from the population - based gcapps study ( p6 = 0.1238 or 128/1034 ) .
p7 , p8 : the brca prevalence in fh - positive ( p7 = 0.09375 ) and fh - negative ( p8 = 0.0203 ) individuals is also obtained from the gcapps study in which 12/128 brca carriers detected were fh - positive and 15/740 were fh - negative .
p9 : reduction in breast cancer risk from rrm in brca carriers not undergoing rrso is taken from the prose study data by rebbeck et al .
p10 : the breast cancer penetrance for brca carriers ( 57% for brca1 and 49% for brca2 ) is taken from a meta - analysis , corrected for ascertainment ( 61 ) .
to simplify the analysis , we have used a composite risk for brca1 and brca2 carriers ( p10 = 0.53 ) weighted for the relative prevalence of brca1 and brca2 fm found in the london aj population .
the brca1 population prevalence is 0.0132 , and brca2 population prevalence is 0.0113 ( gcapps study ) .
the overall risk of breast cancer in brca carriers is calculated as ( ( 0.0132 * 0.57)/2.45 + ( 0.0113 * 0.49)/2.45 ) .
p11 : the risk of breast cancer in a low - risk population is taken from cancer research uk and uk office for national statistics data ( 46,85 ) .
p12 : undergoing rrso can be a complex decision - making process , and rrso rates ranging from 0.3 to 0.75 have been reported in the literature ( 62,71,72,88 ) .
we have used the rrso rate recently reported in high - risk women from london ( p2 = 0.55 ) , as it reflects the views of carriers from a london population and is within the range reported in the literature ( 62 ) .
p13 : the reduction in breast cancer risk in premenopausal women undergoing rrso is taken from a meta - analysis by rebbeck et al .
p14 : reduction in breast cancer risk from rrm in brca carriers undergoing rrso is taken from the prose study data by rebbeck et al .
one - way sensitivity analysis for all probabilities in terms of the incremental cost - effectiveness ratio ( icer ) of population - based screening compared with a family history ( fh)based approach for brca testing .
x - axis : icer : cost (  ) per quality - adjusted life - year ( qaly ) ( discounted ) .
the model is run at both lower and upper values / limits of the 95% confidence interval or range of all probability parameters given in table 1 . 
outcomes to the left of the midline  0  value on the x - axis indicate that the model is cost saving .
fh = family history ; neg = negative ; pos = positive ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
one - way sensitivity analysis for all model costs and utility - score parameters in terms of the incremental cost - effectiveness ratio ( icer ) of population - based screening compared with a family history ( fh)based approach for brca testing .
x - axis : icer : cost (  s ) per quality - adjusted life - year ( qaly ) ( discounted ) .
the model is run at both lower and upper values / limits of the cost and utility - score parameters given in table 2 . 
outcomes to the left of the midline  0  value on the x - axis indicate that the model is cost saving .
this analysis suggests that variation in costs and utility scores do not statistically significantly affect model outcomes .
bc = breast cancer ; fh = family history ; neg = negative ; oc = ovarian cancer ; pos = positive ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
all costs are reported at 2010 prices and where required have been converted using the hospital and community health service index ( 28 ) .
summary of costs used in model ( 2010 prices ) * * all costs were varied by + /-30% in one - way sensitivity analysis .
bnf = british national formulary ; gcapps = genetic cancer prediction through population screening study ; hrt = hormone replacement therapy ; nhs = national health service ; nice = national institutes for health and clinical excellence ; pssru = personal social services research unit ; rrso = risk - reducing salpingo - oophorectomy , rrm = risk - reducing mastectomy .
 cost of genetic counseling / testing : based on pretest counseling time ( 45 minutes ) , 71% genetic testing uptake ( gcapps study ) , and national unit cost assumed for genetic counselling =  44/h of client contact from pssru unit costs of health and social care 2010 ( 89,97 ) .
rrso costs : based on national reference costs for an upper genital tract laparoscopic / endoscopic intermediate procedure ( 90 ) .
costs of hrt ( from bnf ) assume hrt is given from average age of rrso to the average age of menopause ( 51 years ) .
ovarian cancer costs : costs for ovarian cancer diagnosis and treatment were derived from national reference costs and a recent ovarian cancer guideline from nice ( 90,92 ) .
we assumed cost of diagnosis includes a pelvic examination , ultrasound scan , ca125 test , ct scan , percutaneous biopsy , and peritoneal cytology .
the cost of treatment included the reference cost for a lower and upper genital tract very complex major procedure and administration of chemotherapy based on six cycles of carboplatin and paclitaxel treatment .
it was assumed that in years 1 and 2 treated survivors would have a further three consultant visits , a ct scan , and four ca125 tests each year . in years
three to five years postsurgery , it was assumed that survivors would have two consultant visits and two ca125 tests .
we were conservative in our cost estimates and did not include costs for additional investigations , treatment of recurrence , or management of complications in the analysis .
costs for terminal care for ovarian cancer were derived from end - of - life costs for cancer patients based on a report from the national audit office , uk ( 93 ) . in line with nice recommendations ,
breast cancer costs : breast cancer diagnosis and treatment costs were derived predominantly from :  national costing report- implementing nice guidance ( feb 2009 ) ,  which provides estimates of the national cost impact arising from implementation of nice guidelines for diagnosis and treatment of early / locally advanced breast cancer and advanced breast cancer in england , uk ( 47 ) ; from uk department of health nhs reference costs 20102011 ( 90 ) ; the bnf ( 91 ) and other relevant nice guidelines on breast cancer care in general and high risk populations ( 19,50,96 ) .
cost of breast cancer screening : assumes for noncarriers routine mammography ( eight mammograms between 5070 years ) , as per uk nhs breast cancer screening program ( 98 ) .
cost of breast screening for brca carriers is based on annual mammogram from age 40 to 69 years and annual mri from age 30 to 49 years , as per nice guidelines for familial breast cancer ( 19 ) .
cost of rrm : obtained from nhs reference costs ( 90 ) weighted for a 21% complication rate ( 18,95 ) .
cost of breast cancer treatment : in the general population , 10% of breast cancer is noninvasive dcis ; 90% breast cancer is invasive ; 95% of invasive breast cancer is early and locally advanced ( 41% stage 1 , 45% stage 2 , 9% stage 3 [ 4548 ] ) ; 5% of invasive breast cancer is advanced breast cancer ( stage 4 ) ( 4547 ) ; 35% of early and locally advanced breast cancer will progress to advanced breast cancer ( nice costing report , 2009 ) ( 47 ) . in brca carriers , 20% of cancers are dcis and 80% invasive ( 61% stage1 ) ( 18,49 ) .
mean prevalence of axillary lymph node metastasis in early invasive breast cancer is 31.4% ( systematic reviews within the nice breast cancer guideline   and breast cancer clinical outcome measures [ bccom ] project ) .
30% node - positive rate is assumed for brca breast cancer ( based on screening studies in familial breast cancer , breast cancer case series , and early breast cancer trialists collaborative group data ) ( 49,100103 ) .
cost of sentinel lymph node biopsy ( slnb ) : from nice national costing report ( 47 ) .
slnb for staging axilla for early invasive breast cancer and no evidence of lymph node involvement on ultrasound ( us)/negative us  guided biopsy ( 73% of invasive cancers ) .
cost of axillary lymph node dissection ( alnd ) : assumed to be 25% of cost of breast surgery , as per nice guideline development group recommendation ( 47 ) , undertaken for lymph node  positive cancers ( 31% early and locally advanced invasive cancers ) ( 47,96 ) .
breast surgery costs : this includes costs of breast conserving surgery ( assumed for all noninvasive cancers , and 75% of early / locally advanced [ stage 13 ] invasive cancers ) ; and costs of mastectomy with reconstruction ( for 25% early / locally advanced cancers ) .
radiotherapy and chemotherapy : invasive breast cancers that are not low risk ( 99,104,105 ) receive adjuvant treatment in line with nice guidelines .
costs include radiotherapy costs for 60% of early invasive / locally advanced , radiotherapy and chemotherapy costs for 40% early invasive / locally advanced , and chemotherapy costs for all advanced cancers .
radiotherapy costs include planning and 40gy , 15 times over three weeks ( nice guidelines ) or palliative treatment , taken form national nhs reference costs ( 90 ) .
chemotherapy costs ( based on polychemotherapy ) ( 100 ) include administration costs , costs of 1 and 2 line therapy , and toxicity from nice guidelines ( 47,50 ) .
all costs are adjusted for brca breast cancers for difference in stage at presentation and 20% cancers being noninvasive .
70% general population invasive breast cancers are er - positive ; 15% early invasive breast cancers and 25% advanced breast cancers are her2-positive ( 50,96 ) .
27% brca1 and 67% brca2 breast cancers are er - positive ; 5% brca1 and 14% brca2 breast cancers are her2-positive ( 101103,106108 ) .
er and her2 testing costs are obtained from a local nhs trust and included for all breast cancers .
endocrine therapy costs : as per nice guidelines ( 47,96 ) , er - positive invasive breast cancers receive tamoxifen 20mg / day ( premenopausal)/ anastrazole 1mg / day ( postmenopausal ) for five years : costs from the bnf ( 91 ) .
biphosphonate costs : 74% patients with advanced breast cancer will develop bone metastases , and 65% patients with bone metastases are offered bisphosphonates ( 47,109,110 ) . as per nice guidelines , costs ( from bnf )
assume that 50% patients receive oral clodronate and ibandronic acid , and 50% receive intravenous zoledronic acid or pamidronate ( 47 ) .
cost of trastuzumab : for her2-positive patients , given at three - week intervals for one year or until disease recurrence as per nice guidelines .
35% of early / locally advanced breast cancer progress to advanced breast cancer ( nice guidelines ) ( 47 ) .
recurrence rates for early / locally advanced breast cancer ( from the us national surgical adjuvant breast and bowel project [ nsabp ] ) : 15.9% for node - positive ( 111 ) and 11% for node - negative ( 112 ) breast cancer : composite recurrence rate = 12.6% ( weighted for 31% node - positive and 69% node - negative disease ) .
recurrence rate for advanced / metastatic breast cancer is 66% ( 34% relapse free five - year survival ) ( 52 ) .
costs include a progression rate of 35% from early and locally advanced to advanced disease ( 47 ) , and 66% relapse rate for advanced disease ( 52 ) .
costs for terminal care for breast cancer were derived from end - of - life costs for cancer patients based on a report from the national audit office , uk ( 93 ) . in line with nice recommendations , future healthcare costs not associated with breast cancer were not considered ( 25 ) .
chemoprevention ( sensitivity analysis ) : tamoxifen / raloxifene for five years ( 19,23 ) , from bnf ( 91 ) .
life expectancy for women not developing cancer ( age 53 years ) was based on life - tables from the office of national statistics ( 29 ) .
the mean age for breast / ovarian cancer onset was age 41.7/51.5 years for brca1 and 45.6/58.9 years for brca2 aj women , respectively ( 30 ) . to simplify the analysis
, we used average ages for breast ( 43.5 years ) and ovarian cancer ( 54.9 years ) onset for brca1/brca2 carriers , obtained by assigning weights to the individual ages of onset for the relative population prevalence of brca1 and brca2 fm ( ( 1.32*age)/2.45 + ( 1.13*age)/2.45 ) ) .
the mean ages for sporadic breast and ovarian cancer in aj - women were 57 years and 63 years , respectively ( 3133 ) . in the absence of aj - specific survival data ,
five - year survival rates were assumed to be the same as the general uk population ( 34 ) .
this model incorporates potential survival differences between brca1 , brca2 , and sporadic ovarian cancers ( 35,36 ) .
no statistically significant survival difference between brca and sporadic breast cancers has been reported ( 37,38 ) . for ovarian cancer ,
the five - year survival for brca1 is 44% ( 95% confidence interval [ ci ] = 40% to 48% ) and for brca2 52% ( 95% ci = 46% to 58% ) ( 35 ) , giving a composite five - year survival for brca1+brca2 ( weighted by brca1 and brca2 prevalence ) of 0.477 ( ( 0.44 * 1.32/2.45)+(0.52 * 1.13/2.45 ) ) .
after five years survival , the probability of death was assumed to be the same as the general population .
qaly is a measurement that expresses changes in length of life , while at the same time incorporating reductions in quality - of - life .
calculation of qalys requires knowledge of quality - of - life adjustment or utility weights for each health state in the model .
utility weights are an indication of an individual s preference for specific health states where 1 equals perfect health and 0 equals death .
a dutch study found no measurable impact on generic quality - of - life in high - risk women undergoing rrso ( 39 ) .
havrilesky ( 40 ) reported detailed utility estimates related to various health states following ovarian cancer treatment using visual analogue scale and time - trade - off ( tto ) methods .
as visual scales for comparing health state preferences are subject to inherent biases and are generally less accurate ( 41 ) , we utilized the tto scores .
we assumed 70% of women present with ovarian cancer at advanced stages ( 42,43 ) , with a lower utility score for a new diagnosis at 0.55 ( sd = 0.29 ) , while the remainder presenting at early stages have a higher utility score of 0.81 ( sd = 0.26 ) .
the end - stage - of - life utility score , where ovarian cancer patients did not survive the next year , was 0.16 ( sd = 0.25 ) .
of those that survived initial chemotherapy , the chance of recurrence with early disease was 10.5% annually ( 44 ) , and with advanced disease this would be 20.6% ( 42 ) . for women with recurrent disease ,
the mean utility value was 0.5 ( range = 0.40.61 ) , and for women in remission the utility value was 0.83 ( sd = 0.25 ) ( 40 ) . of general population breast cancer ,
10% is noninvasive / dcis , 90% is invasive , 95% of invasive cancer is early and locally advanced ( 41% = stage 1 , 45% = stage 2 , 9% = stage 3 ) ( 4548 ) , and 5% is advanced ( stage 4 ) ( 4547 ) . in brca carriers ,
20% of cancers were dcis and 80% invasive ( 61% = stage 1 ) ( 18,49 ) .
utility weights for breast cancer were assumed as follows : advanced breast cancer was 0.65 , early or locally advanced breast cancer was 0.71 , remission was 0.81 , recurrence was 0.45 ; these were obtained from nice guidelines ( 50,51 ) . for those who survived initial chemotherapy ,
the chance of breast cancer recurrence / progression with early or locally advanced disease was 35% ( 47 ) , and for recurrence with advanced disease it was 66% ( 52 ) . for each branch of the decision model , the probability of being in each branch
the total costs and effects in terms of life - years and qalys were then estimated by weighting the values for each branch by the probability of being in each branch .
the incremental cost - effectiveness ratio ( icer ) was estimated by dividing the difference in cost by the difference in effect .
cost b)/(effect a  effect b ) . by comparing this icer with the cost - effectiveness threshold used by nice (  20000-30000/qaly ) ( 53 ) , it was possible to determine whether or not population screening for all women was cost - effective compared with fh - based testing . to explore uncertainty in the results and robustness of the model ,
a one - way sensitivity analysis was undertaken by varying each parameter in the model and then rerunning the model to assess the impact on overall results .
probabilities and utility scores were varied according to their 95% confidence intervals / range , where available , or by + /-10% , and costs were varied by + /-30% . in addition to the one - way sensitivity results , a probabilistic sensitivity analysis ( psa ) was undertaken as recommended by nice methods guidance ( 25,54 ) .
any variation in model parameters / variables is likely to occur in parallel rather than independently of each other . in the psa all variables
we assigned costs a gamma distribution , probabilities a beta distribution , and utilities a log - normal distribution as suggested in the literature ( 55 ) .
the results of 1000 simulations were plotted on a cost - effectiveness acceptability curve showing the proportion of simulations that indicated that the intervention was cost - effective at different willingness - to - pay thresholds .
other scenarios also explored included : 1 ) breast cancer prophylaxis with serms ( tamoxifen / raloxifene ) in brca carriers ( 19,23 ) and 2 ) women opting for genetic testing at age 50 years ( average age of menopause ) with a median age for rrso and rrm at 54 years ( just below the weighted average age of ovarian cancer onset in brca1/brca2 carriers ) .
all pathway probabilities for the model are presented and explained in table 1 . a one - way sensitivity analysis involved rerunning the model at both lower and upper values / limits of the 95% confidence interval or range of all probability parameters ( table 1 ) used in the model ( figures 2 and 3 ) .
cancer incidence was estimated by summing the probabilities of pathways ending in ovarian or breast cancer .
the total population impact was estimated by multiplying the results per woman by 81224 ( 0.71 * 114400 ) .
probabilities of different pathways in the model * * ci = confidence interval ; fh = family history ; fm = founder mutations ; gcapps = genetic cancer prediction through population screening study ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
p1 : the probability of carrying a brca fm in the aj population ( p1 = 0.0245 ) is taken from the gcapps study , as it provides uk - based data and is consistent with reports from other countries ( 2,86 ) .
p2 : the probability that brca1/2 carrier will undergo rrm is taken from an analysis of uk brca1/2 carriers by evans et al .
2009 . a composite uptake rate ( p2 = 0.52 ) for brca1 ( 60% rrm rate ) and brca2 ( 43% rrm rate ) carriers weighted for the relative prevalence of brca1 and brca2 fm found in the london aj population was computed ( 71 ) .
p3 : the reduction in ovarian cancer risk obtained from rrso ( p3 = 0.96 ) is taken from previous studies , which report a 4% residual risk of primary peritoneal cancer following rrso ( 20 ) .
p4 : a wide range of ovarian cancer risks have been reported for brca carriers , with higher penetrance estimates found in carriers ascertained from high - risk families with multiple cancer cases ( 87 ) .
our analysis uses ovarian cancer penetrance figures ( 40% for brca1 , 18% for brca2 ) from a meta - analysis , corrected for ascertainment ( 61 ) . to simplify the analysis , we have used a composite risk for brca1 and brca2 carriers ( p4 = 0.2987 ) , weighted for the relative prevalence of brca1 and brca2 fm found in the london aj population . the brca1 population prevalence is 0.0132 , and brca2 population prevalence is 0.0113 ( gcapps study ) .
the overall risk of ovarian cancer in brca carriers is calculated as ( ( 0.0132 * 0.4)/2.45 + ( 0.0113 * 0.18)/2.45 ) .
p5 : the risk of ovarian cancer in a low - risk population ( p5 = 0.0185 ) is obtained from cancer research uk ( 84 ) .
p6 : the probability of having a strong fh of cancer fulfilling the current clinical criteria ( fh - positive ) is obtained from the population - based gcapps study ( p6 = 0.1238 or 128/1034 ) .
p7 , p8 : the brca prevalence in fh - positive ( p7 = 0.09375 ) and fh - negative ( p8 = 0.0203 ) individuals is also obtained from the gcapps study in which 12/128 brca carriers detected were fh - positive and 15/740 were fh - negative .
p9 : reduction in breast cancer risk from rrm in brca carriers not undergoing rrso is taken from the prose study data by rebbeck et al . ,
p10 : the breast cancer penetrance for brca carriers ( 57% for brca1 and 49% for brca2 ) is taken from a meta - analysis , corrected for ascertainment ( 61 ) . to simplify the analysis , we have used a composite risk for brca1 and brca2 carriers ( p10 = 0.53 ) weighted for the relative prevalence of brca1 and brca2 fm found in the london aj population .
the brca1 population prevalence is 0.0132 , and brca2 population prevalence is 0.0113 ( gcapps study ) .
the overall risk of breast cancer in brca carriers is calculated as ( ( 0.0132 * 0.57)/2.45 + ( 0.0113 * 0.49)/2.45 ) .
p11 : the risk of breast cancer in a low - risk population is taken from cancer research uk and uk office for national statistics data ( 46,85 ) .
p12 : undergoing rrso can be a complex decision - making process , and rrso rates ranging from 0.3 to 0.75 have been reported in the literature ( 62,71,72,88 ) .
we have used the rrso rate recently reported in high - risk women from london ( p2 = 0.55 ) , as it reflects the views of carriers from a london population and is within the range reported in the literature ( 62 ) .
p13 : the reduction in breast cancer risk in premenopausal women undergoing rrso is taken from a meta - analysis by rebbeck et al .
p14 : reduction in breast cancer risk from rrm in brca carriers undergoing rrso is taken from the prose study data by rebbeck et al .
one - way sensitivity analysis for all probabilities in terms of the incremental cost - effectiveness ratio ( icer ) of population - based screening compared with a family history ( fh)based approach for brca testing .
x - axis : icer : cost (  ) per quality - adjusted life - year ( qaly ) ( discounted ) .
the model is run at both lower and upper values / limits of the 95% confidence interval or range of all probability parameters given in table 1 . 
outcomes to the left of the midline  0  value on the x - axis indicate that the model is cost saving .
fh = family history ; neg = negative ; pos = positive ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
one - way sensitivity analysis for all model costs and utility - score parameters in terms of the incremental cost - effectiveness ratio ( icer ) of population - based screening compared with a family history ( fh)based approach for brca testing .
x - axis : icer : cost (  s ) per quality - adjusted life - year ( qaly ) ( discounted ) .
the model is run at both lower and upper values / limits of the cost and utility - score parameters given in table 2 .
outcomes to the left of the midline  0  value on the x - axis indicate that the model is cost saving .
this analysis suggests that variation in costs and utility scores do not statistically significantly affect model outcomes .
bc = breast cancer ; fh = family history ; neg = negative ; oc = ovarian cancer ; pos = positive ; rrso = risk - reducing salpingo - oophorectomy ; rrm = risk - reducing mastectomy .
all costs are reported at 2010 prices and where required have been converted using the hospital and community health service index ( 28 ) .
summary of costs used in model ( 2010 prices ) * * all costs were varied by + /-30% in one - way sensitivity analysis .
bnf = british national formulary ; gcapps = genetic cancer prediction through population screening study ; hrt = hormone replacement therapy ; nhs = national health service ; nice = national institutes for health and clinical excellence ; pssru = personal social services research unit ; rrso = risk - reducing salpingo - oophorectomy , rrm = risk - reducing mastectomy .
 cost of genetic counseling / testing : based on pretest counseling time ( 45 minutes ) , 71% genetic testing uptake ( gcapps study ) , and national unit cost assumed for genetic counselling =  44/h of client contact from pssru unit costs of health and social care 2010 ( 89,97 ) .
rrso costs : based on national reference costs for an upper genital tract laparoscopic / endoscopic intermediate procedure ( 90 ) .
costs of hrt ( from bnf ) assume hrt is given from average age of rrso to the average age of menopause ( 51 years ) .
ovarian cancer costs : costs for ovarian cancer diagnosis and treatment were derived from national reference costs and a recent ovarian cancer guideline from nice ( 90,92 ) .
we assumed cost of diagnosis includes a pelvic examination , ultrasound scan , ca125 test , ct scan , percutaneous biopsy , and peritoneal cytology .
the cost of treatment included the reference cost for a lower and upper genital tract very complex major procedure and administration of chemotherapy based on six cycles of carboplatin and paclitaxel treatment .
it was assumed that in years 1 and 2 treated survivors would have a further three consultant visits , a ct scan , and four ca125 tests each year . in years
three to five years postsurgery , it was assumed that survivors would have two consultant visits and two ca125 tests .
we were conservative in our cost estimates and did not include costs for additional investigations , treatment of recurrence , or management of complications in the analysis .
costs for terminal care for ovarian cancer were derived from end - of - life costs for cancer patients based on a report from the national audit office , uk ( 93 ) . in line with nice recommendations , future healthcare costs not associated with ovarian cancer were not considered ( 25 ) .
breast cancer costs : breast cancer diagnosis and treatment costs were derived predominantly from :  national costing report- implementing nice guidance ( feb 2009 ) ,  which provides estimates of the national cost impact arising from implementation of nice guidelines for diagnosis and treatment of early / locally advanced breast cancer and advanced breast cancer in england , uk ( 47 ) ; from uk department of health nhs reference costs 20102011 ( 90 ) ; the bnf ( 91 ) and other relevant nice guidelines on breast cancer care in general and high risk populations ( 19,50,96 ) .
cost of breast cancer screening : assumes for noncarriers routine mammography ( eight mammograms between 5070 years ) , as per uk nhs breast cancer screening program ( 98 ) .
cost of breast screening for brca carriers is based on annual mammogram from age 40 to 69 years and annual mri from age 30 to 49 years , as per nice guidelines for familial breast cancer ( 19 ) .
cost of rrm : obtained from nhs reference costs ( 90 ) weighted for a 21% complication rate ( 18,95 ) .
cost of breast cancer treatment : in the general population , 10% of breast cancer is noninvasive dcis ; 90% breast cancer is invasive ; 95% of invasive breast cancer is early and locally advanced ( 41% stage 1 , 45% stage 2 , 9% stage 3 [ 4548 ] ) ; 5% of invasive breast cancer is advanced breast cancer ( stage 4 ) ( 4547 ) ; 35% of early and locally advanced breast cancer will progress to advanced breast cancer ( nice costing report , 2009 ) ( 47 ) .
in brca carriers , 20% of cancers are dcis and 80% invasive ( 61% stage1 ) ( 18,49 ) .
mean prevalence of axillary lymph node metastasis in early invasive breast cancer is 31.4% ( systematic reviews within the nice breast cancer guideline   and breast cancer clinical outcome measures [ bccom ] project ) .
30% node - positive rate is assumed for brca breast cancer ( based on screening studies in familial breast cancer , breast cancer case series , and early breast cancer trialists collaborative group data ) ( 49,100103 ) .
cost of sentinel lymph node biopsy ( slnb ) : from nice national costing report ( 47 ) .
slnb for staging axilla for early invasive breast cancer and no evidence of lymph node involvement on ultrasound ( us)/negative us  guided biopsy ( 73% of invasive cancers ) .
cost of axillary lymph node dissection ( alnd ) : assumed to be 25% of cost of breast surgery , as per nice guideline development group recommendation ( 47 ) , undertaken for lymph node  positive cancers ( 31% early and locally advanced invasive cancers ) ( 47,96 ) .
breast surgery costs : this includes costs of breast conserving surgery ( assumed for all noninvasive cancers , and 75% of early / locally advanced [ stage 13 ] invasive cancers ) ; and costs of mastectomy with reconstruction ( for 25% early / locally advanced cancers ) .
radiotherapy and chemotherapy : invasive breast cancers that are not low risk ( 99,104,105 ) receive adjuvant treatment in line with nice guidelines .
costs include radiotherapy costs for 60% of early invasive / locally advanced , radiotherapy and chemotherapy costs for 40% early invasive / locally advanced , and chemotherapy costs for all advanced cancers .
radiotherapy costs include planning and 40gy , 15 times over three weeks ( nice guidelines ) or palliative treatment , taken form national nhs reference costs ( 90 ) . chemotherapy costs ( based on polychemotherapy )
( 100 ) include administration costs , costs of 1 and 2 line therapy , and toxicity from nice guidelines ( 47,50 ) .
all costs are adjusted for brca breast cancers for difference in stage at presentation and 20% cancers being noninvasive .
70% general population invasive breast cancers are er - positive ; 15% early invasive breast cancers and 25% advanced breast cancers are her2-positive ( 50,96 ) .
27% brca1 and 67% brca2 breast cancers are er - positive ; 5% brca1 and 14% brca2 breast cancers are her2-positive ( 101103,106108 ) .
er and her2 testing costs are obtained from a local nhs trust and included for all breast cancers .
endocrine therapy costs : as per nice guidelines ( 47,96 ) , er - positive invasive breast cancers receive tamoxifen 20mg / day ( premenopausal)/ anastrazole 1mg / day ( postmenopausal ) for five years : costs from the bnf ( 91 ) .
biphosphonate costs : 74% patients with advanced breast cancer will develop bone metastases , and 65% patients with bone metastases are offered bisphosphonates ( 47,109,110 ) .
as per nice guidelines , costs ( from bnf ) assume that 50% patients receive oral clodronate and ibandronic acid , and 50% receive intravenous zoledronic acid or pamidronate ( 47 ) .
cost of trastuzumab : for her2-positive patients , given at three - week intervals for one year or until disease recurrence as per nice guidelines . costs obtained from nice costing report ( 47 ) .
35% of early / locally advanced breast cancer progress to advanced breast cancer ( nice guidelines ) ( 47 ) .
recurrence rates for early / locally advanced breast cancer ( from the us national surgical adjuvant breast and bowel project [ nsabp ] ) : 15.9% for node - positive ( 111 ) and 11% for node - negative ( 112 ) breast cancer : composite recurrence rate = 12.6% ( weighted for 31% node - positive and 69% node - negative disease ) .
recurrence rate for advanced / metastatic breast cancer is 66% ( 34% relapse free five - year survival ) ( 52 ) .
costs include a progression rate of 35% from early and locally advanced to advanced disease ( 47 ) , and 66% relapse rate for advanced disease ( 52 ) .
costs for terminal care for breast cancer were derived from end - of - life costs for cancer patients based on a report from the national audit office , uk ( 93 ) . in line with nice recommendations ,
chemoprevention ( sensitivity analysis ) : tamoxifen / raloxifene for five years ( 19,23 ) , from bnf ( 91 ) .
life expectancy for women not developing cancer ( age 53 years ) was based on life - tables from the office of national statistics ( 29 ) .
the mean age for breast / ovarian cancer onset was age 41.7/51.5 years for brca1 and 45.6/58.9 years for brca2 aj women , respectively ( 30 ) . to simplify the analysis
, we used average ages for breast ( 43.5 years ) and ovarian cancer ( 54.9 years ) onset for brca1/brca2 carriers , obtained by assigning weights to the individual ages of onset for the relative population prevalence of brca1 and brca2 fm ( ( 1.32*age)/2.45 + ( 1.13*age)/2.45 ) ) .
the mean ages for sporadic breast and ovarian cancer in aj - women were 57 years and 63 years , respectively ( 3133 ) . in the absence of aj - specific survival data ,
five - year survival rates were assumed to be the same as the general uk population ( 34 ) .
this model incorporates potential survival differences between brca1 , brca2 , and sporadic ovarian cancers ( 35,36 ) .
no statistically significant survival difference between brca and sporadic breast cancers has been reported ( 37,38 ) . for ovarian cancer ,
the five - year survival for brca1 is 44% ( 95% confidence interval [ ci ] = 40% to 48% ) and for brca2 52% ( 95% ci = 46% to 58% ) ( 35 ) , giving a composite five - year survival for brca1+brca2 ( weighted by brca1 and brca2 prevalence ) of 0.477 ( ( 0.44 * 1.32/2.45)+(0.52 * 1.13/2.45 ) ) .
after five years survival , the probability of death was assumed to be the same as the general population .
qaly is a measurement that expresses changes in length of life , while at the same time incorporating reductions in quality - of - life .
calculation of qalys requires knowledge of quality - of - life adjustment or utility weights for each health state in the model .
utility weights are an indication of an individual s preference for specific health states where 1 equals perfect health and 0 equals death .
a dutch study found no measurable impact on generic quality - of - life in high - risk women undergoing rrso ( 39 ) .
havrilesky ( 40 ) reported detailed utility estimates related to various health states following ovarian cancer treatment using visual analogue scale and time - trade - off ( tto ) methods .
as visual scales for comparing health state preferences are subject to inherent biases and are generally less accurate ( 41 ) , we utilized the tto scores .
we assumed 70% of women present with ovarian cancer at advanced stages ( 42,43 ) , with a lower utility score for a new diagnosis at 0.55 ( sd = 0.29 ) , while the remainder presenting at early stages have a higher utility score of 0.81 ( sd = 0.26 ) .
the end - stage - of - life utility score , where ovarian cancer patients did not survive the next year , was 0.16 ( sd = 0.25 ) .
of those that survived initial chemotherapy , the chance of recurrence with early disease was 10.5% annually ( 44 ) , and with advanced disease this would be 20.6% ( 42 ) . for women with recurrent disease ,
the mean utility value was 0.5 ( range = 0.40.61 ) , and for women in remission the utility value was 0.83 ( sd = 0.25 ) ( 40 ) . of general population breast cancer , 10% is noninvasive / dcis , 90% is invasive , 95% of invasive cancer is early and locally advanced ( 41% = stage 1 , 45% = stage 2 , 9% = stage 3 ) ( 4548 ) , and 5% is advanced ( stage 4 ) ( 4547 ) . in brca carriers ,
20% of cancers were dcis and 80% invasive ( 61% = stage 1 ) ( 18,49 ) .
utility weights for breast cancer were assumed as follows : advanced breast cancer was 0.65 , early or locally advanced breast cancer was 0.71 , remission was 0.81 , recurrence was 0.45 ; these were obtained from nice guidelines ( 50,51 ) . for those who survived initial chemotherapy ,
the chance of breast cancer recurrence / progression with early or locally advanced disease was 35% ( 47 ) , and for recurrence with advanced disease it was 66% ( 52 ) .
for each branch of the decision model , the probability of being in each branch was calculated by multiplying together the path probabilities . the total costs and effects in terms of life - years and qalys
were then estimated by weighting the values for each branch by the probability of being in each branch . the incremental cost - effectiveness ratio ( icer )
cost b)/(effect a  effect b ) . by comparing this icer with the cost - effectiveness threshold used by nice (  20000-30000/qaly ) ( 53 ) , it was possible to determine whether or not population screening for all women was cost - effective compared with fh - based testing . to explore uncertainty in the results and robustness of the model ,
a one - way sensitivity analysis was undertaken by varying each parameter in the model and then rerunning the model to assess the impact on overall results .
probabilities and utility scores were varied according to their 95% confidence intervals / range , where available , or by + /-10% , and costs were varied by + /-30% .
in addition to the one - way sensitivity results , a probabilistic sensitivity analysis ( psa ) was undertaken as recommended by nice methods guidance ( 25,54 ) .
any variation in model parameters / variables is likely to occur in parallel rather than independently of each other . in the psa all variables
we assigned costs a gamma distribution , probabilities a beta distribution , and utilities a log - normal distribution as suggested in the literature ( 55 ) .
the results of 1000 simulations were plotted on a cost - effectiveness acceptability curve showing the proportion of simulations that indicated that the intervention was cost - effective at different willingness - to - pay thresholds .
other scenarios also explored included : 1 ) breast cancer prophylaxis with serms ( tamoxifen / raloxifene ) in brca carriers ( 19,23 ) and 2 ) women opting for genetic testing at age 50 years ( average age of menopause ) with a median age for rrso and rrm at 54 years ( just below the weighted average age of ovarian cancer onset in brca1/brca2 carriers ) .
the discounted and undiscounted lifetime costs , life - years , and qalys for each branch in the decision model are given in table 3 .
overall , a population - screening approach saved more life - years ( 0.090 ) and qalys ( 0.101 ) than an fh - based approach .
this difference equated to 33 days gain in life expectancy for aj women using a population - screening strategy compared with an fh - based one .
discounted results show a smaller overall gain in life - years and qalys and overall cost difference , as discounting adjusts costs and outcomes that occur in the future and the cost savings generated through prevention of future ovarian cancer cases is valued less .
the baseline discounted icer was -2079 per qaly , indicating that population - based screening not only saves more qalys but is also cost saving and is highly cost - effective in aj women .
population - based screening also lowered ovarian cancer incidence by 0.34% ( from 2.49% to 2.15% ) and lowered breast cancer incidence by 0.62% ( from 13.31% to 12.69% ) . assuming that 71% of the estimated 114000 aj women in the uk ( 26,27 ) undergo testing , the overall impact of a population - based strategy is a reduction in ovarian cancer and breast cancer by 276 and 508 cases , respectively , at a discounted cost savings of  3.7 million .
should the entire population undergo testing , the number of cancers potentially prevented would increase to 388 for ovarian and 715 for breast cancers at a discounted cost savings of  5.2 million .
model outcomes for costs , life - years , and quality - adjusted life - years ( qalys ) , undiscounted and discounted * cancer incidence .
bc = breast cancer ; fh = family history ; neg = negative ; oc = ovarian cancer ; pos = positive ; ps = population screening ; qaly = quality - adjusted life - year ; rrso = risk - reducing salpingo - oophorectomy , rrm = risk - reducing mastectomy .
the results of the one - way sensitivity analysis ( figures 2,3 ) indicate that the upper / lower utility values , costs , penetrance estimates , and rate of uptake of preventive / risk - reducing surgery have little influence on the overall results , and the model is cost saving at both upper and lower limits of these variables .
however , the model is highly sensitive to the overall brca prevalence and brca prevalence in fh - negative women ( figure 2 ) . at the lower limits of overall brca prevalence and brca prevalence in fh - positive individuals , the intervention was still just cost saving at -183/qaly and -631/qaly , respectively . at the lowest value for brca prevalence in fh - negative women ,
the icer equals  3877 per qaly , well under the nice threshold of  20000 to  30000 per qaly , indicating that population screening was still cost - effective , but no longer cost saving . at the highest brca prevalence rates in fh - positive and fh - negative women , the intervention was both more effective and cost saving
the probabilistic sensitivity analysis results ( figure 4 ) shows that at a threshold of  20000 94% of simulations indicate that population screening in aj women is a cost - effective intervention compared with current nhs policy .
a scenario incorporating breast cancer prophylaxis with tamoxifen ( premenopausal)/raloxifene ( postmenopausal ) in brca carriers , as recently recommended by nice ( 19 ) , achieved a greater cost savings per qaly of -2472 for population - based screening compared with fh - based testing . a further scenario where unaffected women age 50 years
were screened for brca mutations ( with a median age for rrso and rrm = 54 years ) , also achieved a higher cost savings per qaly of -2946 .
probabilistic sensitivity analysis in which all model parameters / variables are varied simultaneously across their distributions to further explore model uncertainty .
x - axis : incremental cost - effectiveness ratio in terms of cost (  s)/quality - adjusted life - year .
the results of 1000 simulations were plotted on a cost - effectiveness acceptability curve showing the proportion of simulations ( y - axis ) , which indicated that the intervention was cost - effective at different willingness - to - pay thresholds ( x - axis ) .
the solid red line marks the proportion of simulations found to be cost - effective at the  20 000 threshold used by nice .
according to nice , a cost - effectiveness analysis comparing the relative health outcomes and costs of interventions is the preferred form of economic evaluation , and qaly is the most suitable determinant of health benefit , reflecting both mortality and health - related quality - of - life effects ( 25 ) .
this analysis focused on whether the cost differential between different interventions / strategies is worthwhile in terms of changes in health outcomes .
our decision analysis model addressed the topical issue of cost - effectiveness of a new population - based brca testing strategy in aj women , made possible by identification of aj founder mutations and advances in the efficiency / cost of technology for mutation detection .
our finding that a population screening program implemented in uk aj women older than age 30 years will be cost saving compared with the current fh - based one has important implications for clinical care , population / public health , and for health care providers and commissioners .
there is potential within the uk for reduction of the number of ovarian cancers by 276 and breast cancers by 508 , combined with overall cost savings of  3.7 million .
should the entire relevant uk population undergo testing , the number of cancers potentially prevented would increase to 388 for ovarian and 715 for breast cancer at a discounted cost savings of  5.2 million .
this compares favorably with a number of interventions routinely used in clinical practice , which , while saving lives , cost more . for instance , the icer for breast screening in brca1/brca2 carriers age 35 to 49 years recommended by nice ( 56 ) is  11700(mri alone ) or  15300 ( mri+mammography ) per case of cancer detected ( 57 ) .
the icer for paclitaxel and cisplatin for primary treatment of ovarian cancer ranges between $ 6600 and $ 22000 per life - year gained ( 58,59 ) .
this is the first report comparing cost - effectiveness of population screening for founder mutations of brca1/2 with the current standard of care .
our analysis incorporates impact on both breast and ovarian cancer risk and fulfills various requirements suggested by nice for health - economic decision - making .
the  time horizon  in our analysis is long enough to reflect important differences in costs and outcomes ( 25 ) .
we use current best practice as a comparator , qalys to measure health outcomes , a 3.5% discount rate on costs and health outcomes , and , as far as possible , directly obtained population - based data for parameters in the analysis ( 25 ) .
this is the first model to incorporate brca prevalence in fh - negative individuals , and probabilities used in the model are consistent with other reports in the literature ( 2,60 ) .
a comparison of population - screening for brca carriers vs no screening reported an icer of $ 8300 per qaly ( 17 ) .
this higher value compared with the cost savings in our study could be attributable to our lower costs of testing , higher health care costs in the united states compared with the uk , and the beneficial impact of breast cancer prevention found in our study but not evaluated by the earlier study ( 17 ) .
another advantage of our model is that it also includes genetic counseling costs , which would be a key component of any population - based testing strategy .
this approach facilitates reflection of the positive and negative consequences of genetic testing and permits participants to make informed decisions based on their own values and opinions . in order to minimize overestimating benefits of population - based screening
, we have been conservative in our use of ovarian and breast cancer penetrance estimates ( corrected for ascertainment ) ( 61 ) , as well as our costs for ovarian and breast cancer diagnosis and treatment , by including a minimal subset of baseline costs .
we did not include all costs for additional investigations , treatment of recurrence , or management of complications .
the deterministic sensitivity analysis permitted scrutiny of model outcomes and identification of variables that exert the most influence ( figures 2 and 3 ) .
the 95% confidence limits for probabilities explored in our sensitivity analysis were quite wide , adding to the strength of the results .
the lack of statistically significant effect on outcome despite 30% variation in costs indicates that costs of counseling , treatment , and prevention are less important in influencing the overall results .
brca prevalence rates ( p1 , p8 ) emerged as the key variables of influence , given the higher model sensitivity to uncertainties around these values ( figure 2 ) .
that the model remains largely cost saving despite probabilities varying widely is reassuring . even at low prevalence rates in fh - positive or fh - negative individuals ,
population testing remained cost - effective compared with the nice threshold of  20000 to  30000 per qaly ( 53 ) . though we used an rrso risk - reduction estimate ( 0.96 ) based on the residual risk of ppc ( 20 ) , a lower rate of 0.8 ( 21 ) assessed in the sensitivity analysis showed it was still cost saving .
rrso rates vary with time , menopausal status , age , and parity ( 62 ) .
it is encouraging that even at low ( 0.3 ) rrso rates , the model remains cost saving ( figure 2 ) .
the psa undertaken adds to the robustness of our results and has been recommended by decision - making bodies ( 25 ) .
it permits simultaneous variation in probabilities of all parameters to fully characterize uncertainties in the model and its effect on overall results . that 94% of simulations on psa were cost - effective reconfirms the health - economic benefit of a population - based approach to genetic testing .
it does not incorporate any potential reduction in qaly following rrso . although rrso is associated with worse menopausal symptoms and sexual function compared with women undergoing screening , no difference in generic quality - of - life
has been reported ( 39,63,64 ) rrso has also been linked with a higher risk of cardiovascular disease ( 65,66 ) and osteoporosis .
we felt that these downsides in premenopausal women may be balanced by the decrease in vasomotor symptoms , cardiovascular sequelae , and improved sexual function and osteo - protection seen with hormone replacement therapy ( hrt ) ( 63,65,6769 ) , as well as the reduction in cancer worry , perceived risk , and high overall satisfaction observed following rrso ( 39,63 ) .
rrso also halves the risk of subsequent breast cancer in premenopausal women ( 21 ) , and available evidence suggests that hrt does not alter the statistically significant benefit of reduction in breast cancer risk obtained from bilateral oophorectomy ( 70 ) .
of brca carriers , 21% to 67% undergo risk - reducing mastectomy ( 7173 ) .
addition of risk - reducing mastectomy or screening to rrso further increases life expectancy in brca carriers ( 74 ) .
our model incorporates the impact of breast screening already prevalent in the uk and includes the benefits of reduction in breast cancer risk obtained from rrso ( 21 ) and risk - reducing mastectomy ( rrm ) ( 22 ) .
although a negative impact on sexual pleasure and body image has been reported , no difference over time in sexual habit , discomfort , or activity was documented ( 75 ) .
lack of adverse effects on anxiety , depression , and health - related quality - of - life over time has also been reported ( 18,75,76 ) . additionally ,
any negative effects of rrm could be balanced by findings of significant decreases in anxiety scores , improved social activity ( 75 ) , reports of a majority of women finding rrm results to be consistent with their expectations , and high satisfaction with overall cosmetic results ( 7679 ) .
although it can be hypothesized that fh - positive women may be more likely to adapt to their increased risk while fh - negative women have less of an opportunity to consider / adapt to these issues before being tested , we did not find fh to statistically significantly affect quality - of - life outcomes in our gcapps trial .
not all of those undergoing genetic counseling will opt for genetic testing , and a reduced genetic testing uptake rate is built into the model costs . a total of 1034 ( 71% )
of 1450 people who made a genetic counseling appointment in the gcapps study underwent brca testing .
fh did not statistically significantly influence uptake of testing in our population - based trial ; hence , uptake using either fh or population approaches in our decision model is assumed to be similar ( 71% ) .
this estimate lies well within the range of genetic testing rates ( varying from 66%90% ) ( 8083 ) , reported by previous studies of varying ascertainment and sizes .
the intermarriage rate in the jewish community is likely to lead to a fall in brca founder mutation prevalence .
twenty - five percent of jewish marriages in the uk and 44% in the united states are to non - jews , although only 50% of the population is married .
hence , overall , the impact of this is unlikely to affect more than 25% of the population . assuming a brca prevalence of 2.5% for 75% , and 1% for 25% of the population ,
even if brca prevalence were 1% for 50% of the population , the overall population prevalence would be about 1.75% .
these extremes are well within the 95% confidence intervals accounted for in our sensitivity analysis , which shows the model to be cost - effective .
implementation of any national screening program has many challenges and raises important issues of logistics and quality control .
it also requires raising public ( and health professional ) awareness / education , community engagement , and information dissemination via media campaigns , which have an added cost . in the uk ,
screening programs are centrally coordinated by the national screening committee with fail - safe procedures and involve close coordination with gp / primary care and public health physicians .
in addition , there is need for clearly defined downstream secondary and tertiary care pathways , developed in close coordination with clinical genetics teams , breast surgeons , gynecologists , and others responsible for the management of women found to be at high risk .
while these pathways exist for high - risk women , they would need to be expanded prior to program implementation .
it would not be sensible or feasible for all women to undergo pretest counseling in tertiary high - risk cancer genetics clinics within a hospital setting , so a community - based approach would need to be explored .
we have demonstrated that successful recruitment to such a population - based program for pretest counseling and brca testing outside a hospital setting is possible using a community- or high street  based model .
more efficient , acceptable , and cost - effective ways of delivering information on genetic risk will be needed for any population - based testing program to become a reality , and this area should be the focus of further research .
health - economic assessments are critical for determining the appropriateness of resource allocation for cost - intensive population - based interventions .
rising health care costs and the ever - increasing price of new ovarian / breast cancer treatments and drug therapies in a challenging economic environment further magnify the importance of newer cost - effective preventive strategies .
an important advantage of population screening is the ability to identify brca carriers without a strong fh of cancer undetectable by an fh - based approach .
this translates to 2322 additional uk aj women ( population prevalence = 2.03% , 95% ci = 1.14% to 3.32% ) who may benefit from access to screening / preventive options .
the lack of statistically significant difference in short - term outcomes of anxiety , depression , quality - of - life , health anxiety , and overall impact of genetic testing between fh and population - based approaches reconfirms that population - based genetic testing in the majority of jewish people does not harm quality - of - life or psychological well - being , or lead to excessive health concerns ( 11 ) .
the high cost - effectiveness of population - based testing in aj women demonstrated in this analysis combined with the above findings should justify a change in the current paradigm , which is limited to an fh - based approach to brca testing in the aj population .
we conclude that introduction of systematic population testing for aj brca1/2 founder mutations could save both lives and financial resources .
finally , we emphasise that the results from our analysis are related to population - based brca testing in aj women and can not be directly extrapolated to non - aj populations with lower prevalence rates for brca1/2 mutations .
nevertheless , as the cost of testing falls and the acceptance / understanding of this type of health intervention evolves in our societies , it is likely to become an increasingly important area for research and evaluation .
 background : population - based testing for brca1/2 mutations detects the high proportion of carriers not identified by cancer family history ( fh)based testing . 
 we compared the cost - effectiveness of population - based brca testing with the standard fh - based approach in ashkenazi jewish ( aj ) women.methods:a decision - analytic model was developed to compare lifetime costs and effects amongst aj women in the uk of brca founder - mutation testing amongst : 1 ) all women in the population age 30 years or older and 2 ) just those with a strong fh ( 10% mutation risk ) . 
 the model assumes that brca carriers are offered risk - reducing salpingo - oophorectomy and annual mri / mammography screening or risk - reducing mastectomy . 
 model probabilities utilize the genetic cancer prediction through population screening trial / published literature to estimate total costs , effects in terms of quality - adjusted life - years ( qalys ) , cancer incidence , incremental cost - effectiveness ratio ( icer ) , and population impact . 
 costs are reported at 2010 prices . 
 costs / outcomes were discounted at 3.5% . 
 we used deterministic / probabilistic sensitivity analysis ( psa ) to evaluate model uncertainty.results:compared with fh - based testing , population - screening saved 0.090 more life - years and 0.101 more qalys resulting in 33 days gain in life expectancy . 
 population screening was found to be cost saving with a baseline - discounted icer of -2079/qaly . 
 population - based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62% . assuming 71% testing uptake , this leads to 276 fewer ovarian and 508 fewer breast cancer cases . 
 overall , reduction in treatment costs led to a discounted cost savings of  3.7 million . deterministic sensitivity analysis and 
 94% of simulations on psa ( threshold  20000 ) indicated that population screening is cost - effective , compared with current nhs policy.conclusion:population-based screening for brca mutations is highly cost - effective compared with an fh - based approach in aj women age 30 years and older . 
Methods
Probabilities
Costs
Life-years
Quality-Adjusted Life-years (QALYs)
Statistical Analysis
Results
Discussion
Funding
Supplementary Material