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By F. Zarkos. Greenville College.

If you have ever tried to pull together the findings of a dozen or m ore 123 H OW TO READ A PAPER clinical papers into an essay discount cytotec 200 mcg free shipping symptoms congestive heart failure, editorial or sum m ary notes for an exam ination cytotec 100 mcg low cost medicine and health, you will know that it is all too easy to m eander into aspects of the subject which you never intended to cover. The question addressed by a system atic review needs to be defined very precisely, since the reviewer m ust m ake a dichotom ous (yes/no) decision as to whether each potentially relevant paper will be included or, alternatively, rejected as "irrelevant". The question "D o anticoagulants prevent strokes in patients with atrial fibrillation? D oes "atrial fibrillation" include both rheum atic and non-rheum atic form s (which are known to be associated with very different risks of stroke) and does it include interm ittent atrial fibrillation (m y grandfather, for exam ple, used to go into this arrhythm ia for a few hours whenever he drank coffee and would have counted as a "grey case" in any trial)? D oes "stroke" include both ischaem ic stroke (caused by a blocked blood vessel in the brain) and haem orrhagic stroke (caused by a burst blood vessel)? And, talking of burst blood vessels, shouldn’t we be weighing the side effects of anticoagulants against their possible benefits? Should true anticoagulants such as heparin and warfarin be com pared with placebo or with other drugs that reduce the clotting tendency of the blood, such as aspirin and related products? Finally, should the review cover trials on patients who have already had a previous stroke or transient ischaem ic attack (a m ild stroke which gets better within 24 hours) or should it be lim ited to trials on patients without these m ajor risk factors for a further stroke? The "sim ple" question posed earlier is becom ing unanswerable, and we m ust refine it as follows. As I explained in Chapter 2, searching the 124 PAPERS TH AT SU M M ARISE OTH ER PAPERS M edline database for relevant articles is a very sophisticated science and even the best M edline search will m iss im portant papers, for which the reviewer m ust approach the other databases listed in section 2. In the search for trials to include in a review, the scrupulous avoidance of linguistic im perialism is a scientific as well as a political im perative. As m uch weight m ust be given, for exam ple, to the expressions "Eine Placebo-kontrolierte D oppel-blindstudie" and "une étude random isée a double insu face au placebo" as to "a double blind, random ised controlled trial"! Even when all this has been done, the system atic reviewer’s search for m aterial has hardly begun. As Paul Knipschild and his colleagues showed when they searched for trials on vitam in C and cold prevention, their electronic databases only gave them 22 of their final total of 61 trials. Another 39 trials were uncovered by handsearching the m anual Index Medicus database (14 trials not identified previously), searching the references of the trials identified in M edline (15 m ore trials), the references of the references (nine further trials), and the references of the references of the references (one additional trial not identified by any of the previous searches). After all, Knipschild and his team found that only one of the trials not identified in M edline m et stringent criteria for m ethodological quality and ultim ately contributed to their system atic review of vitam in C in cold prevention. Chapters 3 and 4 and Appendix 1 of this book provide som e checklists for assessing whether a paper should be rejected outright on m ethodological grounds. But given that only around 1% of clinical trials are said to be beyond criticism in term s of m ethodology, the practical question is how to ensure that a "sm all but perfectly form ed" study is given the weight it deserves in relation to a larger study whose m ethods are adequate but m ore open to criticism. H ence, one of the tasks of a system atic reviewer is to draw up a list of criteria, including both generic and particular aspects of quality, against which to judge each trial. In theory, a com posite num erical score could be calculated which would reflect "overall m ethodological quality". In reality, however, care should be taken in developing such scores since there is no gold standard for the "true" m ethodological quality of a trial11 and such com posite scores are probably neither valid nor reliable in practice. If you don’t understand what this question m eans, look up the tongue in cheek paper by Carl Counsell and colleagues in the Christm as 1994 issue of the BMJ, which "proved" an entirely spurious relationship between the result of shaking a dice and the outcom e of an acute stroke. H owever, the sim ulation of a num ber of perfectly plausible events in the process of m etaanalysis – such as the exclusion of several of the "negative" trials through publication bias (see section 3. You cannot, of course, cure anyone of a stroke by rolling a dice, but if these sim ulated results pertained to a genuine m edical controversy (such as which groups of postm enopausal wom en should take horm one replacem ent therapy or whether breech babies should routinely be delivered by caesarean section), how 127 H OW TO READ A PAPER would you spot these subtle biases? W hat if the authors of the system atic review had changed the inclusion criteria? W hat if all the unaccounted for patients in a trial were assum ed to have died (or been cured)? If you find that fiddling with the data like this in various ways m akes little or no difference to the review’s overall results, you can assum e that the review’s conclusions are relatively robust. If, however, the key findings disappear when any of the what ifs change, the conclusions should be expressed far m ore cautiously and you should hesitate before changing your practice in the light of them. Question 5 Have the numerical results been interpreted with common sense and due regard to the broader aspects of the problem? As the next section shows, it is easy to be "phased" by the figures and graphs in a system atic review.

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In this study the N staging accuracy increased to 80% with the use of multiplanar reconstruction discount cytotec 100 mcg fast delivery medications band. Improving CT spatial and contrast resolu- tion combined with the use of arterial phase imaging and multiplanar reconstruction for bowel wall assessment may lead to increased diagnos- tic accuracy of local CRC staging generic 200mcg cytotec otc medications rheumatoid arthritis. However, if there is a family history of FAP, then screening beginning at puberty is recom- mended. Cost-Effectiveness Evidence from several studies suggests that screening for, detecting, and removing CRC and precancerous polyps can reduce CRC incidence and related mortality. Accordingly, analyses have demonstrated that screening for CRC by any method is cost-effective when compared with no screen- ing. The incremental cost-effectiveness ratio (ICER) for commonly consid- ered strategies lies between $10,000 and $25,000 per life-year saved (85), which compares favorably with other cancer screening strategies such as annual mammography for women ages 55 to 64 years ($132,000 per life- year saved, in 1998 dollars) (86). However, because different models and modeling assumptions were used and because different strategies were compared, the studies vary widely in their recommended strategies and in their estimates of cost-effectiveness ratios. FOBT combined with a sigmoidoscopy every 5 years (87,88), while others advocate a colonoscopy every 10 years (89,90). McMahon and colleagues (91) compared and reanalyzed the results of three often-cited cost- effectiveness analyses of CRC screening in average-risk populations. The study found that in average-risk individuals, screening with double- contrast barium enema examination every 3 years, or every 5 years with annual fecal occult blood testing, had an ICER of less than $55,600 per life- year saved. However, double-contrast barium enema examination screen- ing every 3 years plus annual fecal occult blood testing had an ICER of more than $100,000 per life-year saved. Colonoscopic screening had an ICER of more than $100,000 per life-year saved, was dominated by other screening strategies, and offered less benefit than did double-contrast barium enema examination screening. However, this analysis assumed a greater sensitivity for DCBE for polyp detection than that determined by Winawer and colleagues (39), thereby introducing a possible bias into their competitive choice analysis; CTC was not included in the analysis. A further study compared cost-effectiveness of CTC to colonoscopy and to no screening, and CTC was found to be cost-effective compared to no screening but not cost-effective compared to colonoscopy (92). The author concluded that CTC must be 54% less expensive than conventional colonoscopy and be performed at 10-year intervals to have equal cost- effectiveness to conventional colonoscopy. This analysis was based on pre- liminary CTC results and may be overly pessimistic, especially given the more recent evidence from Pickhardt and colleagues (50). Clearly, these data demonstrated that sensitivity of CTC for clinically significant lesions is equal to if not better than colonoscopy. In addition, the competitive choice analysis of Sonnenberg (92) did not include the use of CTC for surveillance postpolypectomy. Given the performance of CTC for detec- tion of polyps and relatively low likelihood of average risk individuals developing significant adenomas following colonoscopic resection (39), this omission may have biased the results of their analysis. What Imaging-Based Screening Developments Are on the Horizon that May Improve Compliance with Colorectal Screening? Despite the observed prevalence of polyps and the modification of risk obtained through screening, by current estimates only 15% to 19% of indi- viduals eligible for screening actually undergo colon evaluation of any kind (93). A recent study found that although 80% of the doctors advised screening for CRC to their patients over the age of 50, only about 50% of eligible patients studied had their stool tested for blood and about 30% had a sigmoidoscopy or colonoscopy (94). The perceived discomfort and incon- venience associated with bowel purgation has been identified as a barrier to screening (95,96). Hence, methods to improve patient tolerance may lead to improved compliance with colon cancer screening. Currently, CTC requires a full cathartic bowel preparation, as do sigmoidoscopy and colonoscopy. At present, electronic bowel cleansing using a digital sub- traction technique is being developed (97–101). This "prepless" colonog- raphy requires the patient to ingest a tagging agent such as barium sulfate or nonionic iodinated contrast to tag solid stool and luminal fluid. The Chapter 5 Imaging-Based Screening for Colorectal Cancer 93 bowel contents are thus uniformly opacified allowing subsequent digital subtraction from the image; soft tissue elements such as polyps are unaf- fected. This method potentially obviates bowel catharsis, a major factor in poor compliance with CRC screening.

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