By W. Yugul. Washington & Jefferson College.
Logistic regression estimates the probability of an outcome based on one or more risk factors cheap calan american express. Results of logistic regression analysis are often reported as the odds ratio cheap calan 80 mg, relative risk buy 240 mg calan mastercard, or hazard ratio. For one independent variable of interval-type data and relative risk, this method calculates how much of an increase in the risk of the outcome occurs for each incremental increase in the exposure to the risk fac- tor. An example of this would answer the question “how much additional risk of 364 Essential Evidence-Based Medicine stroke will occur for each increase of 10 mm Hg in systolic blood pressure? For multiple variables, is there some combination of risk factors that will bet- ter predict an outcome than one risk factor alone? The identiﬁcation of signiﬁcant risk factors can be done using multiple regressions or stepwise regression analyses as we discussed in Chapter 29 on clinical prediction rules. Survival analysis In the real world the ultimate outcome is often not known and could be dead as opposed to “so far, so good” or not dead yet. It would be difﬁcult to justify waiting until all patients in a study die so that survival in two treatment or risk groups can be compared. Besides, another common problem with comparing survival between groups occurs in trying to determine what to do with patients who are doing ﬁne but die of an incident unrelated to their medical problem such as death in a motor-vehicle accident of a patent who had a bypass graft 15 years earlier. This will alter the information used in the analysis of time to occlusion with two different types of bypasses. Finally, how should the study handle the patient who simply moves away and is lost to follow-up? The data con- sist of a time interval and a dichotomous variable indicating status, either failure (dead, graft occluded, etc. In the latter case, the patient may still be alive, have died but not from the disease of interest, or been alive when last seen but could not be located again. Early diagnosis may automatically confer longer survival if the time of diagnosis is the start time. This is also called lead-time bias, as discussed in Chapter 28, and is a common problem with screening tests. Censoring bias occurs when one of the treatment groups is more likely to be censored than the other. A survival analysis initially assumes that any patient censoring is independent of the outcome. Survival curves The distribution of survival times is most often displayed as a survivor function, also called a survival curve. It is important to note that “surviving” may indicate things other Survival analysis and studies of prognosis 365 9 x 9 x 8 O 8 O 7 x 7 x 6 6 5 x 5 x 4 4 3 O 3 O 2 x 2 x 1 x 1 x 1970 1975 1977 1980 t=0 t = 5 years Fig. Patient 1 lived longer than everyone except patient 4, although it appears that patient 1 didn’t live so long, since their previous survival (pre-1975) does not count in the analysis. We don’t know how long patient 4 will live since he or she is still alive at the end of the observation period and their data are censored at t = 5 years. Two other patients (3 and 8) are lost to follow-up, and their data are censored early (o). These curves can be deceptive since the number of individuals represented by the curve decreases as time increases. It is key that a statistical analysis is applied at several times to the results of the curves. The actuarial-life-table method measures the length of time from the moment the patient is entered into the study until failure occurs. The product-limit method is a graphic representation of the actuarial-life-table method and is also known as the Kaplan–Meier method. The analysis looks at the period of time, the month or year since the subject entered the study, in which the outcome of interest occurred. There are several tests of equality of these survivor functions or curves that are commonly performed. The Cox proportional-hazard model uses interval data as the inde- pendent variable determining how much the odds of survival are altered by each unit of change in the independent variable. This answers the question of how much the risk of stroke is increased with each increase of 10 mm Hg in mean arterial blood pressure. Further discussion of survival curves and outcome anal- ysis is beyond the scope of this book. Albert Einstein (1879–1955) Learning objectives In this chapter you will learn: r the principles of evaluating meta-analyses and systematic reviews r the concepts of heterogeneity and homogeneity r the use of L’Abbe, forest, and funnel plots´ r measures commonly used in systematic reviews: odds ratios and effect size r how to review a published meta-analysis and use the results to solve a clin- ical problem Background and rationale for performing meta-analysis Over the past 50 years there has been an explosion of research in the medi- cal literature. In the worldwide English-language medical literature alone, there were 1,300 biomedical journals in 1940, while in 2000 there were over 14,000. It has become almost impossible for the individual practitioner to keep up with the literature. This is more frustrating when contradictory studies are published about a given topic.
For example order 120 mg calan visa, monoclonal antibodies can be designed to bind to specific molecules and block their disease-causing effects discount calan on line. However generic calan 80mg overnight delivery, drug developers were unable to use antibodies ob- tained from standard mammalian (usually mouse) cells. Because the molecules differ in structure from one species to the next, mouse antibodies proved to be of very limited benefit in humans. Re- searchers therefore turned their attention to what are known as chimeric and humanised antibodies, where only the recognition regions are based on mouse genes. It is now possible to insert all the human genes required to produce antibodies into laboratory Main avenues of research 45 A new drug class: therapeutic antibodies Mouse Chimeric Humanised Human Each antibody bears on its two short arms identical regions render them harmless. Whereas early therapeutic anti- that recognise a specific foreign structure, to which they bodies were still partly derived from mouse genes (yellow bind. This principle is exploited in therapeutic antibodies in segments), therapeutic antibodies of the latest generation order to recognise pathogenic and other substances and are indistinguishable from their human counterparts. Immunisation Gene transfer Mouse with human Ig genes Human monoclonal antibodies Fully human therapeutic antibodies are obtained by infect- production of immunoglobulins (Ig) with the target for the ing a transgenic mouse that carries human genes for the antibodies that one wishes to produce. As a result, medical science now has at its disposal an arsenal of therapeutic antibodies that are structurally identical to their natural counterparts in the human body. Example MabThera: A good example of a highly effective chimeric an- hope for patients with tibody is the Roche product MabThera/Rituxan lymphoma (rituximab). The target protein of this therapeutic antibody is a receptor located on the surface of B lymphocytes (white blood cells), which in lymphomas grow uncontrollably. The antibodies bind to the cancer cells, marking them out for destruction by the body’s immune system. At the same time rituximab makes the cells more susceptible to certain forms of chemotherapy, thus improving the survival chances of patients who previously had no further therapeutic options fol- lowing unsuccessful chemotherapy. A turbocharger for the Therapeutic antibodies such as rituximab help immune system the patient’s immune system to home in on dis- eased target cells. Main avenues of research 47 Enhanced immune response: modified therapeutic antibodies 120 Engineering of antibody 100 80 60 40 Wildtype antibody 20 Engineered negative 0 control antibody 0 10 20 30 40 50 Antibody concentration (ng/ml) Specifically modified therapeutic antibodies can induce a five to eight times stronger immune response (e. The next drug The next step was to link therapeutic antibodies generation: small with small molecules to form what are known as molecule conjugates small molecule conjugates. Antibodies have a disadvantage that they share with other thera- peutic proteins: they are too bulky to penetrate into the interior of cells. Potential targets are therefore limited to molecules lo- cated outside of or on the surface of the body’s cells. By contrast, many conventional, chemically synthesised small molecule drugs can readily pass through the cell membrane to targets within the cell or even the cell nucleus. Small molecule conjugates combine the specificity of therapeu- tic proteins – especially antibodies –with the broad target range of small molecules. To produce them, researchers have de- veloped complexes, or conjugates, consisting of therapeutic antibodies coupled to low-molecular-weight drugs. In such con- jugates the antibody’s role is to ferry the actual drug directly to its target in the body. Drugs commonly used to destroy cancer cells also attack healthy cells in the body. Once Co plexbinds this occurs, the entire conju- tocell gate is internalised in the cell. In cancer cells the anti- body is digested and releases the small molecule, which Cancercell then destroys the diseased cell. In this way cancer cells Cancercell orzelle can be specifically targeted and adverse effects on Co plexcarries drugintocell healthy cells can be minim- ised. If Entireco plexinsidecell the findings from tests are borne out, the latest gener- ation of these drugs could Cancercell signal a breakthrough not Drugkills cancercell only in cancer therapy but in many other therapeutic Conjugated antibodies combine the specificity of thera- areas where medical science peutic proteins with the broad target range of small mole- has hitherto had to contend cules. The antibodies target a specific structure on the with severe side effects surface of cancer cells. Once the antibody has located its target and bound to it, the conjugated small molecule drug caused by the unspecific is released, penetrates the cancer cell and kills it. Spektrum Akademischer Verlag, Heidelberg, 6th edition 2003 Presentations at a media conference: The Roche Group – one of the world’s leaders in bio- tech, Basel, November 2004 http://www. As well as the therapeutic possibilities it offers, modern biotechnology can lead to novel ways of combating diseases such as diabetes, cancer and rheumatic diseases. For example, early and specific diagnosis, and also tests that can monitor treatment and the course of an illness, can result in more effective treatment of patients. The more doctors know about the causes of diseases, the more ef- fectively they can deal with them. This realisation may sound simple, but translating it into practice remains difficult, be- cause the critical part of treatment is often finding the right diagnosis. It is precisely in this area that biotechnology has made tremendous strides in recent decades. Thus, for example, alleviating pain should not be the only goal when treating patients with chronic pain. It is only when the source of the pain has been identified that steps can be taken to counter it in the long term.
All the major medical journals now require authors to list potential conﬂicts of interest with their submissions buy 240 mg calan with amex. These are important to let the reader know that there may be a greater potential for bias in these studies buy calan 240 mg. However cheap generic calan canada, there are always potential reasons to suspect bias based upon other issues that may not be so apparent. These include the author’s need to “publish or perish,” desire to gain fame, and belief in the correctness of a particular hypothesis. A recent study on the use of bone-marrow transplantation in the treatment of stage 3 breast cancers showed a positive effect of this therapy. However, some time after publi- cation, it was discovered that the author had fabricated some of his results, mak- ing the therapy look better than it actually was. The site gives information about the purpose of the clinical trial, who may participate, locations, and phone numbers for more details. The purpose of the registry is to get the details of the trial published on-line prior to initiation of the trial itself. This way, the researchers cannot spin the results to look better by reporting different outcomes than were originally speciﬁed or by using different methods than originally planned. Most journals will no longer publish trials that are not registered in this or a similar international registry. The question of placebo controls is one ethical issue which is constantly being discussed. Since there are therapies for almost all diseases, is it ever ethical to have a placebo control group? This occurs when the clinician is unsure about the suitability of a therapy and there is no other therapy that works reasonably well to treat the condition. Both the researcher and the patient must be sim- ilarly inclined to choose either the experimental or a standard therapy. Integrity without knowledge is weak and useless, and knowledge without integrity is dangerous and dreadful. This occurred in part as a response to the atroc- ities of Nazi medicine and in part because of the increasing rate of techno- logical advances in medicine. While these issues triggered important reforms, the focus was largely restricted to protection of human experimental subjects. Even cases that were not found to be misconduct increased public and political inter- est in the behavior of researchers. This interest resulted in the development of federally prescribed deﬁnitions of scientiﬁc misconduct. Now there are require- ments that federally funded institutions adopt policies for responding to allega- tions of research fraud and for protecting the whistle-blowers. This was followed by the current requirement that certain researchers be given ethics training with funding from federal research training grants. This initial regulation was scandal-driven and was focused on preventing wrong or improper behavior. As these policies were implemented, it became apparent that this approach was not encouraging proper behavior. This new focus on fostering proper conduct by researchers led to the emergence of the ﬁeld now generally referred to as the responsible conduct of research. This devel- opment is not the invention of the concept of scientiﬁc integrity, but it has sig- niﬁcantly increased the attention bestowed on adherence to existing rules, reg- ulations, guidelines, and commonly accepted professional codes for the proper conduct of research. It has been noted that much of what constitutes responsi- bleconductofresearchwouldbeachievedifwealladheredtothebasiccodeof conduct we learned in kindergarten: play fair, share, and tidy up. A pri- mary source of such evidence is from scientiﬁcally based clinical research. Research must be proposed, conducted, reported, and reviewed responsibly and with integrity. In order for that trust to exist, the consumer of the biomedical literature must be able to assume that the researcher has acted responsibly and conducted the research honestly and objectively. The process of science and proper conduct of evidence-based medicine are equally dependent on the consumption and application of research ﬁndings being conducted with responsibility and integrity. This requires readers to be knowledgeable and open-minded in reading the literature. They must know the factual base and understand the techniques of experimental design, research, and statistical analysis. It is as important that the reader consumes and applies research without bias as it is that the research is conducted and reported without bias. Responsible use of the literature requires that the reader be conscientious in obtaining a broad and representative, if not complete, view of that segment.