Complex Systems & Integrated Learning – v 0.9

PS: This model is primarily based on the theory of Natural Selection and the term 'Rube Goldberg System’ is not written here in the context of ‘irreducible complexity’.

to be continued…

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MP 101: Molecular Programming

It’s happening and I am into it…

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References:

1. PyMOL software, http://pymol.org

2. Molecular Programming Project, CalTech

3. Personal archive

# YouTube direct link

This work by Amin, SB is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 United States License.

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How significant the “significant p-value” is?

With more than 10,000 randomized controlled clinical trials surfacing on PubMed every year, impact of evidence based medicine is becoming quite prevalent in clinical settings. Statistically derived significance of some landmark trials is often translated in routine clinical skills bringing paradigm shift in clinical practice management. Thus, veracity of such trials is becoming more and more critical in recent years to keep health care and quality standards to its optimum and putting patient at no harm.

Recently, expert review committee at American College of Cardiology released common pitfalls of randomized trials which will be published in Journal of American College of Cardiology in the February 2, 2010 issue.¹ The authors, Drs Kaul and Diamond highlight three particular limitations of randomized trials, which they feel are responsible for most misinterpretation of results:

• The strength of evidence is often judged by conventional tests that rely heavily on statistical significance and estimation of confidence intervals (CIs), with less attention paid to the clinical significance or the practical importance of the treatment effects.
• Composite end points are often used to increase the number of outcome events, thereby reducing requisite sample size, but this can undermine the scientific validity of the conclusions drawn from these trials.
• Exploratory subgroup analyses, which are frequently performed, lead to the reporting of chance findings that encourage suboptimal patterns of practice.

Of a particular note, it is an interesting (and important) observation that lack of established guidelines in inferring what magnitude of statistical significance is indeed clinically or practically significant and requiring change in current clinical practice guidelines. i.e. p-value of < 0.05 or < 0.001 or less. Certainly, meta-analysis and multi-center RCTs over a period of time add strength to such p-values but as explained above, RCTs with commonly used design have their pitfalls and they should be carefully designed with inclusion of robust biostatistical models (i.e. Bayesian model, Risk Analysis), estimating minimal clinically important difference based on previously established threshold, etc.

Further recommendations are on how to balance between stringency and feasibility of test and study design and about subgroup analysis. Details cane be found at Medscape.com²

 

Related resources:

1. Kaul S and Diamond GA. Trial and error. How to avoid commonly encountered limitations of published clinical trials.J Am Coll Cardiol 2010; 55:415–27. doi:10.1016/j.jacc.2009.06.065

2. Sue Hughes, How to Get "Clinically Significant" Randomized Trials. HeartWire, Medscape. Jan 25, 2010 Further reading

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On the track: First Oral Medicine for Multiple Sclerosis

A coming year would bring some good news for those 2.5 million patients who suffer from multiple sclerosis (MS) – a chronic, disabling disease by adding first ever oral medications in managing its

remitting-relapsing course. Currently approved therapies for MS are primarily parenteral immunomodulatory and immunosuppressant agents: interferon beta, glatiramer acetate, mitoxantrone and natalizumab. Besides relative non-compliance associated with parenteral drugs, these drugs have peculiar side-effects requiring regular and watchful monitoring of patient. There has been significant research ongoing since last decade on newer targeted immune therapies for MS. i.e. monoclonal antibodies like Daclizumab, Alemtuzumab, Ocrelizumab; vaccine against T-cell (Tovaxin), Estradiol, Teriflunomide, etc. Although many of these experimental drugs have failed in early or late clinical trials, researchers are finally excited to see remarkable success of two new oral agents, namely Cladribine and Fingolimod.

Three Phase III clinical trials (ranging between 2-3 years) published in NEJM on 20-Jan-2010, each involving more than 1000 patients showed significant reduction in disease relapse rate and number of brain lesions as well as slower time to sustained progression of disability.

1. Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial¹
2. FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trial²
3. Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS).³

Compare to placebo, relative risk reduction in the yearly relapse rate was approaching 60% for both drugs. Fingolipid was also found to be superior than intramuscular interferon beta-1a therapy in a 12 month study. Although drug therapy was not associated with significant and serious side effects leading to drug discontinuation, long-term monitoring and post-market surveillance is strongly advised considering their mechanism of action.

These two drugs act differently than current agents, primarily by activation of anti-inflammatory type 2 helper T-cells rather targeting pro-inflammatory type 1 helper T-cells to control elevated auto-immunity. Fingolimod (FTY720, Novartis Inc.) is an oral sphingosine-1-phosphate–receptor modulator which acts by preventing lymphocyte outflow from lymph nodes and reducing infiltration of activated lymphocytes into the central nervous system. It has possible neuroprotective effects. Cladribine is resistant to the enzyme adenosine deaminase, which causes an accumulation of toxic deoxyribonucleotides in lymphocytes, resulting in relatively selective long-term depletion of CD4+ and CD8+ T cells.⁴

Both agents are expected to be in market by early 2011 for extended evaluation as well as to monitor rare side-effects and improve current guidelines for managing multiple sclerosis.

 

References:

1. Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0902533
2. Kappos L, Radue E-W, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0909494
3. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010. DOI: 10.1056/NEJMoa0907839
4. Carroll WM. Oral Therapy for Multiple Sclerosis — Sea Change or Incremental Step? N Engl J Med 2010. DOI: 10.1056/NEJMe0912019

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