***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective To assess the incremental cost and cost-effectiveness of continuous and discontinuous regimens of bevacizumab ( Avastin ) and ranibizumab ( Lucentis ) for neovascular age-related macular degeneration ( nAMD ) from a UK National Health Service ( NHS ) perspective . Design A within-trial cost-utility analysis with a 2-year time horizon , based on a multicentre factorial , non-inferiority r and omised controlled trial . Setting 23 hospital ophthalmology clinics . Participants 610 patients aged ≥50 years with untreated nAMD in the study eye . Interventions 0.5 mg ranibizumab or 1.25 mg bevacizumab given continuously ( monthly ) or discontinuously ( as-needed ) for 2 years . Main outcome measures Quality -adjusted life-years ( QALYs ) . Results Total 2-year costs ranged from £ 3002/patient ( $ 4700 ; 95 % CI £ 2601 to £ 3403 ) for discontinuous bevacizumab to £ 18 590/patient ( $ 29 106 ; 95 % CI £ 18 258 to £ 18 922 ) for continuous ranibizumab . Ranibizumab was significantly more costly  than bevacizumab for both continuous ( + £ 14 989/patient ( $ 23 468 ) ; 95 % CI £ 14 522 to £ 15 456 ; p<0.001 ) and discontinuous treatment ( + £ 8498 ( $ 13 305 ) ; 95 % CI £ 7700 to £ 9295 ; p<0.001 ) , with negligible difference in QALYs . Continuous ranibizumab would only be cost-effective compared with continuous bevacizumab if the NHS were willing to pay £ 3.5 million ( $ 5.5 million ) per additional QALY gained . Patients receiving continuous bevacizumab  accrued higher total costs ( + £ 599 ( $ 938 ) ; 95 % CI £ 91 to £ 1107 ; p=0.021 ) than those receiving discontinuous bevacizumab , but also accrued non-significantly more QALYs ( + 0.020 ; 95 % CI −0.032 to 0.071 ; p=0.452 ) . Continuous bevacizumab therefore cost £ 30 220 ( $ 47 316 ) per QALY gained versus discontinuous bevacizumab . However , bootstrapping demonstrated that if the NHS is willing to pay £ 20 000/QALY gained , there is a 37 % chance that continuous bevacizumab  is cost-effective versus discontinuous bevacizumab . Conclusions Ranibizumab  is not cost-effective compared with bevacizumab , being substantially more costly and producing little or no QALY gain . Discontinuous bevacizumab is likely to be the most cost-effective of the four treatment strategies evaluated in this UK trial , although there is a 37 % chance that continuous bevacizumab is cost-effective . Trial registration number IS RCT N92166560 Abstract Objective To assess the cost effectiveness of adding spinal manipulation , exercise classes , or manipulation followed by exercise ( “ combined treatment ” ) to “ best care ” in general practice for patients consulting with low back pain . Design Stochastic cost utility analysis alongside pragmatic r and omised trial with factorial design . Setting 181 general practice s and 63 community setting s for physical treatments around 14 centres across the United Kingdom . Participants 1287 ( 96 % ) of 1334 trial participants . Main outcome measures Healthcare costs , quality adjusted life years ( QALYs ) , and cost per QALY over 12 months . Results Over one year , mean treatment costs relative to “ best care ” were £ 195 ( $ 360 ; € 279 ; 95 % credibility interval £ 85 to £ 308 ) for manipulation , £ 140 ( £ 3 to £ 278 ) for exercise , and £ 125 ( £ 21 to £ 228 ) for combined treatment . All three active treatments increased participants ' average QALYs compared with best care alone . Each extra QALY that combined treatment yielded relative to best care cost £ 3800 ; in economic terms it had an “ incremental cost effectiveness ratio ” of £ 3800 . Manipulation alone had a ratio of £ 8700 relative to combined treatment . If the NHS was prepared to pay at least £ 10 000 for each extra QALY ( lower than previous recommendations in the United Kingdom ) , manipulation alone would probably be the best strategy . If manipulation was not available , exercise would have an incremental cost effectiveness ratio of £ 8300 relative to best care . Conclusions Spinal manipulation is a cost effective addition to “ best care ” for back pain in general practice . Manipulation alone probably gives better value for money than manipulation followed by exercise Objective An economic evaluation of therapeutic massage , exercise , and lessons in the Alex and er technique for treating persistent back pain . Design Cost consequences study and cost effectiveness analysis at 12 month follow-up of a factorial r and omised controlled trial . Participants 579 patients with chronic or recurrent low back pain recruited from primary care . Interventions Normal care ( control ) , massage , and six or 24 lessons in the Alex and er technique . Half of each group were r and omised to a prescription for exercise from a doctor plus behavioural counselling from a nurse . Main outcome measures Costs to the NHS and to participants . Comparison of costs with Rol and -Morris disability score ( number of activities impaired by pain ) , days in pain , and quality adjusted life years ( QALYs ) . Comparison of NHS costs with QALY gain , using incremental cost effectiveness ratios and cost effectiveness acceptability curves . Results Intervention costs ranged from £ 30 for exercise prescription to £ 596 for 24 lessons in Alex and er technique plus exercise . Cost of health services ranged from £ 50 for 24 lessons in Alex and er technique to £ 124 for exercise . Incremental cost effectiveness analysis of single therapies showed that exercise offered best value ( £ 61 per point on disability score , £ 9 per additional pain-free day , £ 2847 per QALY gain ) . For two-stage therapy , six lessons in Alex and er technique combined with exercise was the best value ( additional £ 64 per point on disability score , £ 43 per additional pain-free day , £ 5332 per QALY gain ) . Conclusions An exercise prescription and six lessons in Alex and er technique alone were both more than 85 % likely to be cost effective at values above £ 20 000 per QALY , but the Alex and er technique performed better than exercise on the full range of outcomes . A combination of six lessons in Alex and er technique lessons followed by exercise was the most effective and cost effective option . How does the Alex and er Technique work ? What are the authors findings about the clinical and cost effectiveness of the treatment ? Watch this video to find out ( 12 mins ) . A field experiment was carried out in Kolda ( southern Senegal ) from July 1986 to July 1988 . Its goals were to : ( 1 ) describe the patterns of mortality of female Guinean goats by age , season and year ; ( 2 ) assess preventive measures against respiratory diseases and gastrointestinal parasitism in reducing mortality ; and ( 3 ) estimate the overall impact of these measures on survival to 1 year of age . Preventive measures for respiratory disease included vaccination against peste des petits ruminants ( PPR ) and pneumonic pasteurellosis ( Pasteurella multocida types A and D ) . Control of gastrointestinal parasites was by deworming does with morantel ( 7.5 mg kg(-1 ) , three times during the rainy season ) . The effects of vaccines and deworming were tested in a r and omised factorial field experiment with villages being the experimental units . A total of 19 villages , 113 goat herds and 1,458 goats were included in the study . Generalised linear models of survival for five cohorts of goats ( defined by five different birth seasons ) used a binomial assumption for the response distribution and a complementary log-log link . Explanatory variables included age , season , year ,  vaccination , deworming  and their interactions . A complex a priori model was built on the basis of previous epidemiological knowledge ; a purpose ly selected set of simpler models was compared to this full model by the Akaike information criterion ( AIC ) and derived statistics . Inference on 1-year survival and treatment effects accounted for model- selection uncertainty . It was carried out with a bootstrap procedure and used information from the whole set of selected models . Large variations in mortality by year and season were observed but no regular seasonal pattern was apparent . Mortality probabilities of kids in dewormed groups decreased quickly after birth , but remained elevated up to 9 months of age in the non-dewormed groups . Deworming lowered the risk of mortality . Vaccination alone was not protective ( except during an observed outbreak of PPR ) Increasing numbers of economic evaluations are conducted alongside r and omised controlled trials . Such studies include  factorial trials  , which r and omise patients to different levels of two or more factors and can therefore evaluate the effect of multiple treatments alone and in combination . Factorial trials can provide increased statistical power or assess interactions between treatments , but raise additional challenges for trial‐based economic evaluations : interactions may occur more commonly for costs and quality ‐adjusted life‐years ( QALYs ) than for clinical endpoints ; economic endpoints raise challenges for transformation and regression analysis ; and both factors must be considered simultaneously to assess which treatment combination represents best value for money . This article aims to examine issues associated with factorial trials that include assessment of costs and /or cost‐effectiveness , describe the methods that can be used to analyse such studies and make recommendations for health economists , statisticians and trialists . A hypothetical worked example is used to illustrate the challenges and demonstrate ways in which economic evaluations of factorial trials may be conducted , and how these methods affect the results and conclusions . Ignoring interactions introduces bias that could result in adopting a treatment that does not make best use of healthcare re sources , while considering all interactions avoids bias but reduces statistical power . We also introduce the concept of the opportunity cost of ignoring interactions as a measure of the bias introduced by not taking account of all interactions . We conclude by offering recommendations for planning , analysing and reporting economic evaluations based on factorial trials , taking increased analysis costs into account . © 2017 The Authors . Statistics in Medicine published by John Wiley & Sons Background The evaluation of more than one intervention in the same r and omised controlled trial can be achieved using a parallel group design . However this requires increased sample size and can be inefficient , especially if there is also interest in considering combinations of the interventions . An alternative may be a factorial trial , where for two interventions participants are allocated to receive neither intervention , one or the other , or both . Factorial trials require special considerations , however , particularly at the design and analysis stages . Discussion Using a 2 × 2 factorial trial as an example , we present a number of issues that should be considered when planning a factorial trial . The main design issue is that of sample size . Factorial trials are most often powered to detect the main effects of interventions , since adequate power to detect plausible interactions requires greatly increased sample sizes . The main analytical issues relate to the investigation of main effects and the interaction between the interventions in appropriate regression models . Presentation of results should reflect the analytical strategy with an emphasis on the principal research questions . We also give an example of how baseline and follow-up data should be presented . Lastly , we discuss the implication s of the design , analytical and presentational issues covered . Summary Difficulties in interpreting the results of factorial trials if an influential interaction is observed is the cost of the potential for efficient , simultaneous consideration of two or more interventions . Factorial trials can in principle be design ed to have adequate power to detect realistic interactions , and in any case they are the only design that allows such effects to be investigated Objectives : State and national tobacco quitlines have exp and ed rapidly and offer a range of services . We examined the effectiveness and cost effectiveness of offering callers single session versus multisession counselling , with or without free nicotine patches . Methods : This 3 × 2 r and omised trial included 4614 Oregon tobacco quitline callers and compared brief ( one 15-minute call ) , moderate ( one 30-minute call and a follow-up call ) and intensive ( five proactive calls ) intervention protocol s , with or without offers of free nicotine patches ( nicotine replacement therapy , NRT ) . Blinded staff assessed tobacco use by phone at 12 months . Results : Abstinence odds ratios were significant for moderate ( OR = 1.22 , CI = 1.01 to 1.48 ) and intensive ( OR = 1.29 , CI = 1.07 to 1.56 ) intervention , and for NRT ( OR = 1.58 , CI = 1.35 to 1.85 ) . Intent to treat quit rates were as follows : brief no NRT ( 12 % ) ; brief NRT ( 17 % ) ; moderate no NRT ( 14 % ) ; moderate NRT ( 20 % ) ; intensive no NRT ( 14 % ) ; and intensive NRT ( 21 % ) . Relative to brief no NRT  , the added costs for each additional quit was $ 2467 for brief NRT , $ 1912 for moderate no NRT , $ 2109 for moderate NRT , $ 2641 for intensive no NRT , and $ 2112 for intensive NRT . Conclusion : Of 
    Output:
    
Simulation work demonstrated that in analyses of factorial RCTs , taking account of all interactions or including interactions above a certain size ( regardless of statistical significance ) minimised the opportunity cost from adopting treatments that do not in fact have the highest true net benefit