Risky Betting for Rating Mild Psoriasis Therapeutic Outcomes: Intra-Class Correlation Coefficients Confirm Low PASI Score Inter-rater Unreliability

GUEST BLOGGERS:
Robert P. Dellavalle and Julie Green

In 1946, the mathematician Stanisław Ulam wondered how many times a 52 card deck would play out successfully in a game of solitaire. Instead of mathematically calculating the solution Ulam empirically played the solitaire one hundred times and observed the results. And thus the Monte Carlo simulation (named after the popular European casino where Stanislaw’s uncle frequently gambled) was born.

Monte Carlo simulations used in space and oil exploration, and many other risky endeavors, predict cost and schedule overruns. So a gambling moniker is appropriate. Increased computer power has made Monte Carlo simulations easier over the years since Ulam used them to help produce nuclear bombs during the Manhattan project. Monte Carlo simulations now model a boggling array of phenomena ranging from predicting the weather, determining the lifetime energy output of wind farms, forecasting the impact of pollution, optimizing winning strategies for games like Battleship and Go, modeling virtual 3D images, and valuing a company’s assets, to optimizing the design of wireless telephone networks.

And why did we spend so much time on calculus in high school?

Monte Carlo simulations are comprised of computational algorithms performed on multiple random samplings. In the recent JID paper by Gourraud and colleagues (Gourraud et al., 2012) the authors examined samplings of theoretical Psoriasis Area Severity Index (PASI) scores.

The PASI was developed to standardize assessment of the severity of psoriasis and changes in severity over time in individual patients. The PASI reflects a mathematical equation that incorporates scaled measurements of psoriasis-related erythema, induration, and scaling on the head, arms, trunk, and legs, which results in a score that ranges from 0 (no disease) to 72 (maximal disease). Because two clinicians evaluating the same patient rarely calculate the same PASI scores, these measurements are at least partially subjective. The PASI scoring system is also too cumbersome for many clinicians to incorporate into daily practice.

Many clinical research protocols have used the PASI scoring system to monitor responses of patients to experimental psoriasis treatments, and determination of efficacy is generally based upon the FDA guideline of at least a 75% improvement in PASI score. Using the Intra-Class Correlation Coefficient (ICC) Gourraud and colleagues confirmed what has long been suspected but hidden by less appropriate statistical methods—that for patients with limited psoriasis (evidenced PASI scores below 20) PASI scores are not reliable measures of therapeutic outcome. These results confirm the need for better therapeutic outcome measures of psoriasis for patients with limited psoriasis (Jensen et al. 2010).

References:

Jensen JD, Fujita M, Dellavalle RP. Validation of Psoriasis Clinical Severity and Outcome Measures: Searching for a Gold Standard. Commentary on: How Good Are Clinical Severity and Outcome Measures for Psoriasis?: Quantitative Evaluation in a Systematic Review by Spuls PI, et al. Arch Dermatol, 2011 Jan;147(1):95-8. PMID: 20855674.

Gourraud, P-A, Le Gall C, Puzenat E (2012) Why Statistics Matter: Limited Inter-Rater Agreement Prevents Using Psoriasis Area and Severity Index as a Unique Determinant of Therapeutic Decision in Psoriasis. J Invest Dermatol epublished 17 May 2012.

Wikipedia, Stanisław Ulam Accessed June 2012

This image was obtained from Flickr, and it is by sskennel.

Small Scales, Big Ideas – Nanodermatology at the Society for Investigative Dermatology

GUEST BLOGGERS:
Jason Chouake, Albert Einstein College of Medicine
David Schairer, Albert Einstein College of Medicine
Adam Friedman, MD, Albert Einstein College of Medicine
Adnan Nasir, MD, PhD University of North Carolina at Chapel Hill

The Nanodermatology Society (NDS) recently held its first meeting in conjunction with the annual meeting of the Society for Investigative Dermatology in Raleigh, North Carolina. Scientists from around the globe met in person to present their research, discuss potential future collaborations, and integrate their knowledge. From the nine presentations, three major themes emerged: nanoscale delivery systems, application of nanotechnology in scientific development and research, and safety of nanotechnology.

The development of nanodelivery systems is a hot area of nanotechnology research. Areas of interest range from nanoparticle platforms that can be used for enhanced wound healing or antimicrobial effects to the development of nanoneedles for drug and vaccine delivery. Two new nanoparticle platforms were presented that show the potential for nanotechnology in wound healing. Dr. Meya Li, from Menicon Co., reviewed data on self assembling peptide hydrogels , demonstrating their potential as a carrier of activating or inhibiting factors of wound healing. David Schairer, a dermatology research fellow from the Albert Einstein College of Medicine, showed how nanoparticles could be used to encapsulate, protect and deliver siRNA to promote accelerated wound healing. Harnessing nanotechnology to develop new antimicrobial agents was also highlighted. Jason Chouake, a dermatology research fellow from the Albert Einstein College of Medicine, reviewed his work using N-acetyl-cysteine-nitric oxide nanoparticles to combat virulent gram positive and negative bacterial species. In line with the role of nanotechnology in the management of infectious diseases, Dr. Geza Erdos, from the University of Pittsburgh, discussed how dissoluble microneedle arrays can be used to deliver activated cargo, such as vaccines, to targeted layers of the skin.

Nanotechnology also enables more efficient and sensitive analysis of genes, and these techniques are already being used to characterize the association between specific genes and diseases. Dr. James T. Elder, from the University of Michigan, discussed how gene chips make it possible to identify infrequent or low risk alleles for psoriasis. It is now possible to test cohorts of up to 30,000 patients and thus obtain the statistical strength to identify these previously elusive alleles. Dr. Elder’s work is already being used by other researchers, like Dr. Antonio Costanzo from the University of Rome. Dr. Costanzo uses nanotechnology in the form of next generation sequencing technology coupled with chromatin immunoprecipitation (Nano-ChIP-seq) to explore the pathogenesis of psoriasis. Nano-ChIP-seq provides 2-3 order of magnitude improvement over conventional ChIP-seq in terms of the number of cells required to generate significant results. Using Nano-ChIP-seq, Dr. Costanzo and his colleagues have shown that IKKα is downregulated in patients with psoriasis, and they have discovered a novel nuclear function of IKKα as a repressor of inflammatory genes in keratinocytes. Both of these researchers highlighted how they capitalize on both the cost saving and data enhancing benefits nanotechnology confers to gene chips.

In light of statements made by the FDA concerning the importance of characterizing the safety of new nanotechnologies for consumer use, Nancy Monteiro-Riviere discussed her work in the toxicological assessment of different nanoparticle platforms. She discussed how standards are slowly being developed to assess the safety of emerging nanotechnologies. When asked whether nanoparticle safety could be evaluated by particle class, Dr. Monteiro Riviere replied, “Each nanoparticle is different and the manufacturing processes as well as the particle itself are important factors that determine the potential toxicity of nanoparticles.” Dr. Monteiro Riviere argued that toxicity assays must be carefully selected, and that one assay is not sufficient to characterize the toxicity of a nanoparticle.

Nanotechnology is being utilized and researched worldwide, and it will continue to be a major target of investigation by both private corporations and academic researchers. The collaboration between industry and academia through the Nanodermatology Society offers great potential for both translational and basic research collaborations. The NDS is a forum where scientists from different countries and settings can meet and develop relationships that involve exchanges among researchers in a field where geography and scientific research have no barriers, providing greater chances of success.

In the words of Charles Darwin:
In the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed.

To find out more about nanodermatology, we recommend the following resources:

1. DeLouise LA. Applications of Nanotechnology in Dermatology. J Invest Dermatol. 2012;132(3):964-975.
2. Blecher K, Nasir A, Friedman A. The growing role of nanotechnology in combating infectious disease. Virulence. 2011;2(5):395-401.
3. Nasir, A, Wang S, and Friedman A. The Emerging Role of Nanotechnology in Sunprotection: An Update. Expert Review Dermatol. 2011; 6(5): 437-439
4. Nasir A. Nanotechnology and dermatology: Part I-potential of nanotechnology. Clinics in Dermatology. 2010;28(4):458-66.
5. Nasir A. Nanotechnology and dermatology: Part II-risks of nanotechnology. Clinics in Dermatology. 2010;28(5):581-
6. Hia J, Nasir A. Photonanodermatology: the interface of photobiology, dermatology and nanotechnology. Photodermatology Photoimmunology & Photomedicine. 2011;27(1):2-9.
7. Nasir A, Friedman A. Nanotechnology and the Nanodermatology Society. Journal of Drugs in Dermatology. 2010;9(7):879-882.
8. Sandoval B. Perspectives on FDA’s Regulation of Nanotechnology: Emerging Challenges and Potential Solutions. Comprehensive Reviews in Food Science and Food Safety. 2009;8(4):375-393.

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Inspirational Daze

Kaleidoscopic vision is the best way to experience the 2012 annual meeting of the Society for Investigative Dermatology (SID). The meeting celebrated the 75th anniversary of the SID, and the spirits of its founders filled the Raleigh, NC convention center. Many of their pictures were on medallion decals in the entrance hall. These decals celebrated the past, and modern QR codes connected the medallions to articles about these individuals and their times.

Another inspirational exhibit was the reproduction of Stephen Rothman’s notebook documenting his displacement from Hungary and his relocation to the University of Chicago, where he performed and recorded pharmacological studies on his own skin.

The oral and poster presentations, many by dermatology residents and fellows from around the world, inspired attendees with new data related to skin biology and skin diseases.

The role of new technologies related to genomic sciences was impressive — everything from immunological mechanisms, to tracing hospital epidemics of serious infectious diseases, to determining the etiology of very rare congenital and genetic conditions that had resisted routine genetic testing were discussed. High school students from the North Carolina School of Science and Mathematics in Durham, NC added to the youthful energy, and the students used the historical medallions on the floor for hopscotch, reminding us that the young think out of the box – and reminding us of the joy of play.

Five days later at the near-by concert Hall, Itzhak Perlman played the Tchaikovsky Violin Concerto in D Major with the North Carolina Symphony Orchestra: another kind of inspirational performance, where the performer and audience were rapturously engaged with a challenging concerto. Using a 300 year old Stradivarius, Perlman captivated the audience, demonstrating that (admittedly, depending on the task) technology need not always be the newest. The performance took the complete commitment of a diligent master performer completely integrated with his supporting orchestra — not very different from the lecturers at the SID, whose orchestras of supporting junior and senior scientists allow their ideas to soar.

May all performers of science and the arts practice hard and play on for their committed audiences, who turn to them for inspiration.

(the image is from Flickr and attributed to SÃ¶ren ‘chucker’ Kuklau)

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