Review of last week What is GINA? what does it forbid? what philosophical positions are in conflict? ApoE variants what are they associated with? how big is the risk of 1 or 2  4 alleles compared to general population? (what would be odds ratio?) is this big enough to change behavior? should you have the right to keep this info pvt.?

what kind of insur. co. is this relevant to? can they ask if you have been tested? what term refers to this situation? what are potential mkt. consequences? what are pot. consequences if law is changed to forbid insur. co. from using this info? what ethical/philosophical principles are in conflict? where do you stand?

Patents What is the social justification for them? Can there be too much or too little patent protection? What are some ways in which Congress/legal system has tried to strike a balance? What is BRCA1? What was patented? Have there been social costs? Social benefits? What did ACLU argue on behalf of “plaintiffs”?

Do you agree with the following ACLU arguments? If true, should they be cause to invalidate a patent? it’s hard to ‘invent around’ a gene patent the patent reduced investigation of mutations prevalent in some racial groups some women couldn’t get a ‘second opinion’ the tests were more expensive than if there were no patent Myriad would not allow other companies to perform tests it was not doing itself patenting ‘comparing’ gene sequences infringes freedom of speech and thought

What did the defendents argue? plaintiff’s don’t have standing NY court does not have jurisdiction plaintiffs shouldn’t be entitled to ‘injunctive relief’ before they infringe USPTO was just doing what Congress asked it to Chakrabarty case and Hand decision justify patenting living things and ‘purified’ natural things What did the judge decide? Do you agree? Why? What will happen next? What may be consequences if decision is upheld or overruled?

Cancer screening – why a controversy over PSA testing? Natural hx of prostate ca PSA test What happens when a PSA test is positive How many lives (life years) are saved… per what (# people tested, years of testing, cost…) What are potential benefits and harms How do you set a threshold for test “positivity” to try to balance benefits and harm What if harms and benefits accrue to different people

Most common cancers in USA (2009) incidencedeaths womenmenwomenmen 1breastprostatelunglung 2lunglungbreastprostate 3coloncoloncoloncolon 4pancreaspancreas 5ovary >10cervixcervix

Prostate cancer biology Who gets it?  5-10% of yr old men develop prostate ca. over 10 year follow-up period  50% of yr old men who die of other causes have prostate ca on autopsy Natural hx of prostate cancer – often (but not always) slow time from onset to symptoms  10 yrs time from symptoms to death  15 yrs Will screening identify large # of men with early cancers that would never cause symptoms during their lives? = “excess diagnosis” rate, est.  40% for PSA test

What is done if PSA is positive? bx What is done if bx is positive (assume no mets)? surgical prostatectomy +/- radiation complications urinary incontinence (?  20%) sexual impotence (?  50%) Should PSA screening be offered routinely, given 40% excess diagnosis and high complication rate? Should decision be up to patient?

How should level for “+” test be determined? PSA = glycoprotein produced mainly by the prostate elevated in prostate cancer and other prostate disorders > 4ng/ml in  20% of men with prostate ca (sens.) < 4ng/ml in  90% of men without prostate ca (spec.) How would specificity and sensitivity change for >, < 8ng/ml <, < 2ng/ml?

Digression on sensitivity, specificity, etc. Condition positivenegative TestpositiveTPFP pos. pred. val. TP/(TP+FP) negativeFNTN neg. pred. val. TN/(FN+TN) sensitivityspecificity TP/(TP+FN)TN/(FP+FN) prevalence = # with disease/total # = (TP+FN) / (TP+FP+TN+FN)

Example 1: 203 people screened by fecal blood test for bowel cancer cancer (confirmed by biopsy) pos.neg. fecal pos.TP=2FP=18 pos. pred. val. 2/(2+18)=.1 bloodneg.FN=1TN=182 neg. “ “ 182/(182+1)=.99 sensitivityspecificity 2/(2+1)=.67182/(18+182)=.91 prevalence = (2+1)/( ) = 3/203

Example 2: 236 women with BRCA mutations screened annually by 3 modalities. Which is most sensitive? JAMA 292: 1317 (‘04) How predictive is a + MRI compared to a + mammogram?

A little math: Note 4 #’s (TP, FP, TN, FN) determine 5 ratios: spec., sens. pos. pred. value (ppv) neg. pred. value (npv) prevalence (prev.) Are any ratios are affected by N = TP+FP+TN+FN? No, so ratios determined by 3 indep. variables Can express any 2 ratios in terms of other 3 Which ratios are (are not) affected by prevalence? ppv and npv are; (spec. and sens. are not) Sometimes convenient to express ppv, npv in terms of sens., spec. and prevalence

Choosing a cut-off value for a screening test, e.g. PSA for prostate ca, affects sens. and spec. of test Sens. and spec. usually anti-correlated sensitivity 1- specificity specificity x x x x Receiver-operator charac- teristic (ROC) curve showing sens. and spec. at different cut-off values high cut-off low cut-off Fx of time assay is wrong

JAMA 294:66 (2005) X4ng/ml ROC for PSA test *At end of study, all men recommended to have biopsy

For many years, PSA test assumed to be good idea find and treat the cancer before it spreads European study  70,000 men > 50 yo screened by PSA test every 4yrs + 90,000 controls, followed for  10 yrs screenedcontrols prostate cancer rate8.2%4.8% “excess” cancers found( /8.2) = 41% prostate ca deaths per 10,000 person yrs relative death rate3.5/4.1 =.85 confidence interval (p=.04 no diff.)

For every life saved,1410 men screened 48 cancers treated ? ~20 unnecessarily My rough est. of cost per life year saved from Euro. study PSA tests1480 x 2 x $50148K Biopsies.3 x 1480 x $ K Treatment48 x $10,000480K if 10 yrs life gained/life saved ~100K/yr life # unnecessary treatments (40%)19 # unnecss. cases of urinary incont.4 # unnecc. cases of sex. impotence10

Do harms outweigh benefits? How can you decide? Is it fair to put cost on “harms” and combine them with other costs -> new cost/QALY? Should choice of PSA test be left up to patient? How would you propose to give patient adequate information? What about patient’s who don’t want to (or can’t) evaluate data?

Add uncertainties of clinical studies … US study  32,000 men screened annually, roughly equal # controls, about 10 yr follow-up period, found no difference in survival (prostate ca mortality slightly higher in screened group, 2.0 vs 1.7/10,000 person yrs) 50% of US controls got PSA tests anyway, which may explain smaller “excess” cancer rate in US study (20% vs 40%)

Conclusion – don’t assume screening is always good Similar issues – weighing benefits vs harms – in screening for other cancers Next week – breast cancer screening balancing benefits vs harms ethical issues who decides consequences of “expert” recommendations Take-home mid-term on Blackboard, due in 2 weeks Think about final project; me as soon as you have some ideas – I may have helpful suggestions