Thursday, September 22, 2016

Treatment of Iron Deficiency - Risks

Iron overdose as a cause of a high anion gap metabolic acidosis

Now, iron is usually mentioned as an important cause of metabolic acidosis, and there is a warm spot reserved for it in the “MUDPILES” mnemonic. An impressionable person might be inclined to believe that iron contributes to the high anion gap metabolic acidosis by dissociating into unmeasured anions, much like the toxic alcohols. However, that would be wildly inaccurate, because iron is a cation.


The acidosis here is multifactorial. Some textbooks (Fowler’s Handbook on the Toxicology of Metals) suggest that the acidosis is mainly due to the physicochemical effects of the iron ion itself. Other sources (Goldfranks Manual of Toxicologic Emergencies) attribute the acidosis to a raised lactate, of which not all is generated by direct effects of the iron, but rather due to the fluid loss (from an ulcerated gut), cardiogenic shock (due to the myocardial mitochondrial toxicity) and fulminant hepatic failure. On top of that, a fair portion of  the lactic acidosis is due to the direct mitochondrial toxicity of iron in all tissues.
 

Monday, September 19, 2016

Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value

Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value


tableIn this example, two columns indicate the actual condition of the subjects, diseased or non-diseased. The rows indicate the results of the test, positive or negative.
Cell A contains true positives, subjects with the disease and positive test results. Cell D subjects do not have the disease and the test agrees.
A good test will have minimal numbers in cells B and C.  Cell B identifies individuals without disease but for whom the test indicates 'disease'. These are false positives. Cell C  has the false negatives.
If these results are from a population-based study, prevalence can be calculated as follows:
  • Prevalence of Disease=  Tdisease/ Total × 100
The population used for the study influences the prevalence calculation.
Sensitivity is the probability that a test will indicate 'disease' among those with the disease:
  • Sensitivity: A/(A+C) × 100
Specificity is the fraction of those without disease who will have a negative test result:
  • Specificity: D/(D+B) × 100
Sensitivity and specificity are characteristics of the test. The population does not affect the results.
A clinician and a patient have a different question: what is the chance that a person with a positive test truly has the disease? If the subject is in the first row in the table above, what is the probability of being in cell A as compared to cell B? A clinician calculates across the row as follows:
  • Positive Predictive Value: A/(A+B) × 100
  • Negative Predictive Value: D/(D+C) × 100
Positive and negative predictive values are influenced by the prevalence of disease in the population that is being tested. If we  test in a high prevalence setting, it is more likely that persons who test positive truly have disease than if the test is performed in a population with low prevalence..
Let's see how this works out with some numbers...

Hypothetical Example 1 - Screening Test A

table100 people are tested for disease. 15 people have the disease;  85 people are not diseased.  So,  prevalence is 15%:
  • Prevalence of Disease:
    Tdisease/ Total × 100,
    15/100 × 100 = 15%
Sensitivity is two-thirds, so the test is able to detect two-thirds of the people with disease. The test misses one-third of the people who have disease.
  • Sensitivity:
    A/(A + C) × 100
    10/15 × 100 = 67%
The test has 53% specificity. In other words, 45 persons out of 85 persons with negative results are truly negative and 40 individuals test positive for a disease which they do not have.
  • Specificity:
    D/(D + B) × 100
    45/85 × 100 = 53%
The sensivity and specificity are characteristics of this test. For a clinician, however, the important fact is among the people who test positive, only 20% actually have the disease.
  • Positive Predictive Value:
    A/(A + B) × 100
    10/50 × 100 = 20%
For those that test negative, 90% do not have the disease.
  • Negative Predictive Value:
    D/(D + C) × 100
    45/50 × 100 = 90%
Now, let's change the prevalence..

Hypothetical Example 2 - Increased Prevalence, Same Test

This time we  use the same test, but in a different population, a disease prevalence of 30%.
  • tablePrevalence of Disease:
    Tdisease/ Total × 10
    30/100 × 100 = 30%
We maintain the same sensitivity and specificity because these are characteristic of this test.
  • Sensitivity:
    A/(A + C) × 100
    20/30 × 100 = 67%
  • Specificity:
    D/(D + B) × 100
    37/70 × 100 = 53%
Now let's calculate the predictive values:
  • Positive Predictive Value:
    A/(A + B) × 100
    20/53 × 100 = 38%
  • Negative Predictive Value:
    D/(D + C) × 100
    37/47 × 100 = 79%
Using the same test in a population with higher prevalence increases  positive predictive value. Conversely, increased prevalence results in decreased negative predictive value. When considering predictive values of diagnostic or screening tests, recognize the influence of the prevalence of disease. The figure below depicts the relationship between disease prevalence and predictive value in a test with 95% sensitivity and 95% specificity:
graph
Relationship between disease prevalence and predictive value in a test with 95% sensitivity and 85% specificity.
(From Mausner JS, Kramer S: Mausner and Bahn Epidemiology: An Introductory Text. Philadelphia, WB Saunders, 1985, p. 221.)

Think About It!

Come up with an answer to this question and then click on the icon to the left to reveal the answer.
Under what circumstance would you really want to minimize the false positives?
 answerMinimizing false positives is important when the costs or risks of followup therapy are high and the disease itself is not life-threatening...prostate cancer in elderly men is one example; as another, obstetricians must consider the potential harm from a false positive maternal serum AFP test (which may be followed up with amniocentesis, ultrasonography and increased fetal surveillance as well as producing anxiety for the parents and labeling of the unborn child), against potential benefit.

Think About It!

Come up with an answer to this question and then click on the icon to the left to reveal the answer.
When would you want to minimize the false negatives?
answer: We don’t want many false negative if the disease is often asymptomatic and
  1. is serious, progresses quickly and can be treated more effectively at early stages OR
  2. easily spreads from one person to another

What is a good test in a population?  Actually, all tests have advantages and disadvantages, such that no test is perfect.  There is no free lunch in disease screening and early detection.