Research Techniques Made Simple: SYSTEMATIC REVIEWS AND META-ANALYSIS Q&A

Below are Questions and Answers relating to the Research Techniques Made Simple article “The Role of Systematic Reviews and Meta-Analysis in Dermatology” (J Invest Derm 132:e2, 2012; doi:10.1038/jid.2012.392)

 

QUESTIONS:

                             

  1. GRADE and SORT describe which of the following?
    1. Techniques for assessing the risk of bias in individual studies
    2. Guidelines on how to report systematic reviews and meta-analyses
    3. Types of fixed-effect models used in statistical meta-anlaysis
    4. Methods for rating the strength of clinical recommendations

 

  1. Which of the following is true regarding random-effects models?
    1. They are generally consider more appropriate if the I2 value is > 40%
    2. They are rarely used in meta-analysis
    3. They are often employed to assess the risk of bias in individual studies
    4. They are most appropriate when between-study heterogeneity is low

 

 

 

ANSWERS:

 

1. d: Methods for rating the strength of clinical recommendations

 

2. a: They are generally consider more appropriate if the I2 value is > 40%

 

Dermatologists: “Beat thy scalpels into scopes” ; or at least sheath them more often in favor of bedside microscopy

Guest Blogger: Allan C. Halpern, Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY

Dermatology has been among the slowest of medical specialties to embrace non-invasive diagnostic techniques. This is quite understandable given that the skin is so accessible to simple visual inspection, dermatologists appropriately pride themselves on their skills as visual morphologists, and skin biopsies are -easily performed procedures. Of these assertions, the first is true (but also underscores why skin is so amenable to the use of optical diagnostic aids), the second is increasingly inapplicable (as dermatologists increasingly trade on their diagnostic acumen to sharpen their procedural skills), and the third is a matter of perspective. As the saying goes: “What’s the definition of minor surgery? Surgery on somebody else”.  In my own experience, the same dermatologist who readily performs biopsies becomes quite gun shy when the scalpel is pointed at his or her own nose.

I confess that I write this missive out of respect and admiration for Lowell Goldsmith, who invited me to share my views and try to provoke those of others in response to a recent article entitled “In Vivo Confocal Microscopy (CLSM) for Diagnosis of Melanoma and Basal Cell Carcinoma Using a Two Step Method,” written by my esteemed colleagues from Australia and Italy (Guitera et al, 2012). I am  a blog virgin, but have a lifelong clinical and research interest in non-invasive skin imaging (including CLSM), and have worked closely with the authors of the aforementioned paper.

The paper is the most recent in a series of articles by close collaborators who have played a critical role in defining the diagnostic features for malignancy as seen under confocal microscopy and who have most convincingly demonstrated the diagnostic accuracy of the technique. As in the case of dermoscopy, the first clinical application of cutaneous CLSM was to melanoma followed by a broader application to other skin malignancies and non-malignant conditions. What the body of work demonstrates is that CLSM adds significantly to diagnostic accuracy above and beyond dermoscopy, and should be considered as an adjunct to, rather than a replacement for, naked eye examination and dermoscopy.

It is quite astounding that through the wizardry of physics and optical engineering a device using a light source less powerful than a laser pointer along with a few optical tricks can visualize individual cells down to the level of the papillary dermis. The magic underlying the technique is dependent on subtle differences in the optical properties of the target, making some cells invisible and others bright enough to make out nuclei. While an appreciation of these subtleties is required, the average dermatologist has enough training in dermatopathology to interpret the images after limited instruction. Working under the assumption that more diagnostic data is clinically desirable, one would expect dermatologists to be clamoring to get these machines into their practices. Those working with these techniques realize that there will always be specificity and sensitivity tradeoffs with any diagnostic process.  The reality is that while I anticipate that some such technology will be routinely used by dermatologists in the future, there are many barriers to the rapid diffusion of the technique.  Based on lessons learned from total body photography and dermoscopy, these barriers will include an inherent resistance to change, associated front end expenses, and perhaps most importantly- logistic and reimbursement considerations. As an example, it has taken over 20 years to win over the average dermatologist to adopt dermoscopy in their practices despite the low cost and ease of use of the device along with convincing and consistent data on its clinical utility. While I know many dermatologists who still haven’t trained in the use of a dermatoscope, I don’t know a single one who has used one for a significant length of time without becoming reliant on it.

The price of entry with CLSM is significantly higher than with dermoscopy in terms of finances, logistics, and learning curve. This has slowed diffusion into practice which in turn impedes the evolution of insights into the use of the technique. Thanks to technical breakthroughs, significant progress is being made to simplify (and hence reduce the cost) of the technology while simultaneously improving the logistics of size and ease of use. As with minimally invasive surgery, the technique will have to overcome cultural as well as technical hurdles prior to dissemination, and similarly, patient demand will likely play an important role in the process should it achieve wide use.

Whether CLSM or some other new technology, one would hope that doctors will embrace technologic improvements in care. It would be distressing to think that the next generation of dermatologists will rely as heavily on biopsies as we do. While critical analysis and appropriate vetting of any new clinical technique should be a requirement for broad adoption, this has often not been the case. Conversely, the broad implementation of many medical breakthroughs has often been tragically delayed by a cultural resistance on the part of ‘organized medicine’.  Hopefully, the younger generation of dermatologists can be energized to see new imaging technologies as enabling rather than threatening and to do the studies that will bring the best of these technologies to bear on our patients’ well being sooner rather than later. To this end (here’s the shameless plug that was my secondary motivation for writing the piece), I invite anyone reading this blog to the tri-society meeting of the International Dermoscopy Society (IDS), the International Society for Digital Imaging of the Skin (ISDIS) and the International Confocal Working Group (ICWG) which will be held in Miami on March 1st at 5:30pm in conjunction with the annual meeting of the American Academy of Dermatology– website links below.

 

REFERENCES:

Guitera P, Menzies SW. State of the art of diagnostic technology for early-stage melanoma. Expert Rev Anticancer Ther. 2011 11(5):715-23.

Guitera P, Menzies SW, Longo C. In Vivo Confocal Microscopy (CLSM) for Diagnosis of Melanoma and Basal Cell Carcinoma Using a Two Step Method J Invest Derm 132:2386-2394, 2012

Braun RP, Rabinovitz H, Tzu JE, Marghoob AA. Dermoscopy research–an update. Semin Cutan Med Surg. 2009 28(3):165-71

 

IMAGE CREDIT:

Original image by Aesop on Flickr.com, used here through a creative commons license

Sand Fly Giveth, Taketh, and Make Me Thinketh

This image by the Armed Forces Pest Management Board was downloaded from Flickr; it is used under a Creative Commons License.

Reading widely in journals allows random inputs that percolate in the interstices of the mind and eventually help solve problems. Reading journals may not seem as exciting as random inputs from wandering the streets of Rome or trekking through the Grand Tetons, but journals are handy, never-ending sources of stimulation. I realize that there is an opportunity cost to reading journals and learning about things that do not lead to a new grant or paying the rent.  Nevertheless, I have always valued the time I spend bathing in the pure stimulation of science. A recent publication in JID stimulated me to think about parasitic diseases and their vectors (Gomes et al, 2012).

A purified sand-fly salivary gland protein was inoculated into mice and protected the mice when they were bitten by sandflies infected with Leishmania. The lymphocytes of Knock-out B-cell deficient mice lymphocytes received protection, but mice treated with anti-helper cell antibodies developed ulcerative leishmaniasis after being bitten. The protection by salivary protein inoculation was not complete, since Leishmania were  present in the skin of protected mice. It has been known for about 15 years that mice bitten by sand-flies not carrying Leishmania are protected when subsequently bitten by infected sand-flies.

I doubt that this is a unique confluence of organism, vector, and host, and we can consider the described ”vaccination” to have broader protective mechanisms. Usually, vaccination is considered through the spyglass of specificity, aimed at the perfect immune response of the host. There may be other ways of skinning the  infection cat that deserve contemplation; the protective response of vaccination deserves a wide-angle rather than a telescopic lens.

LJM11 the salivary protein that alters the immune response also generated antibodies that cross-react with the epithelial cell surface molecule desmoglein-1(DSG1) that is a target of of pathogenic molecules in Brazilian pemphigius foliiaceus (Qian et al, 2012). The common epitope for DSG-1 and LJM11 is conformational in nature and not determined by the amino acid sequences of the tqwo molecules. . Whether this finding has anything in common with the effect of LJM11 on lymphocytes remains to be determined.

 

REFERENCES

Gomes R, Oliveira F, Teixeira C, et al (2012) Immunity to Sand Fly Salivary Protein LJM11 Modulates Host Response to Vector-Transmitted Leishmania Conferring Ulcer-Free Protection. J Invest Dermatol doi: 10.1038/jid.2012.205

Qian Y, Jeong JS, Maldonado M,  et al (2012) Cutting edge:Brazilian pemphigus foliaceus anti-desmoglein I autoantibodies cross-react with Sand fly salivary LJM11 antigen. J Immunology 189:1535-1539