Is the incidence of sickle cell disease rising?

In 1949, Linus Pauling and coworkers showed that sickle cell anemia is a disease produced by an inherited alteration in hemoglobin, producing a molecule that is separable from normal hemoglobin, by electrophoris. Electrophoresis is still used to distinguish sickle hemoglobin from normal hemoglobin.

In 1956, Vernon Ingram and J.A. Hunt sequenced the hemoglobin protein molecule (normal and sickle cell) and showed that the inherited alteration in sickle cell hemoglobin is due to a single amino acid substitution in the protein sequence.

Because sickle cell hemoglobin can be detected by a simple blood test, it was assumed, back in the 1950s, that new cases of this disease would be prevented through testing, followed by genetic counseling. Today, there are a number of private and public organizations that work to reduce the incidence of sickle cell disease.

I have been interested in knowing whether sickle cell incidence is decreasing in the U.S. population. Despite Pubmed and web searches, I have not been able to find a single data source on the subject.

I decided to investigate using the CDC (U.S. Centers for Disease Control and Prevention) mortality data sets. In a separate document, I've provided methods for acquiring and analyzing the CDC public use mortality files.

For the current study, I downloaded the mortality files for the years 1996, 1999, 2002, and 2004, all of which contain de-identified records listing multiple conditions, coded in ICD-10 (International Classification of Disease, version 10), for the underlying causes of death and other significant conditions, found on U.S. death certificates.

I parsed through every record (about 5 Gigabytes of raw data), and compiled the following results.

In 1996, U.S. cases with sickle cell disease in death certificates is 708
In 1996, U.S. rate of sickle cell disease in death certificates is 30.54 per 100,000

In 1999, U.S. cases with sickle cell disease in death certificates is 799
In 1999, U.S. rate of sickle cell disease in death certificates is 33.36 per 100,000

In 2002, U.S. cases with sickle cell disease in death certificates is 827
In 2002, U.S. rate of sickle cell disease in death certificates is 33.79 per 100,000

In 2004, U.S. cases with sickle cell disease in death certificates is 876
In 2004, U.S. rate of sickle cell disease in death certificates is 36.47 per 100,000

For all four years examined, there has been a steady, increasing trend in the number of death certificates listing sickle cell disease as a cause of death or a significant condition at the time of death. Likewise, the overall rate (per 100,000 certificates) has steadily increased in every sampled year, covering 1996 to 2004.

Does this mean that efforts to reduce the incidence of sickle cell disease have failed? No. Death certificate data is unreliable. Whether a doctor thinks of adding sickle cell disease as a medical condition, on the death certificate, may depend on a variety of factors (as discussed previously). However, when you're dealing with very large numbers, trends usually reflect reality.

The best data would be natality incidence rates, by year, measured between about 1960 and the present. However, I have not been able to find that kind of data, and the CDC mortality files may be the next-best option.

For those interested in conducting an independent analysis of the same data, here are the locations of the files that I downloaded by anonymous ftp from the CDC server (ftp.cdc.gov)

1999
/pub/Health_Statistics/NCHS/Datasets/mortality

2002, 2004
/pub/Health_Statistics/NCHS/Datasets/DVS/mortality

1996 data file that combines icd9 and 1cd10 data
/pub/Health_Statistics/NCHS/Datasets/Comparability/icd9_icd10

If anyone has access to more reliable data, or a different set of results, please add a comment to this blog.

- © 2008 Jules Berman

As with all of my scripts, lists, web sites, and blog entries, the following disclaimer applies. This material is provided by its creator, Jules J. Berman, "as is", without warranty of any kind, expressed or implied, including but not limited to the warranties of merchantability, fitness for a particular purpose and noninfringement. in no event shall the author or copyright holder be liable for any claim, damages or other liability, whether in an action of contract, tort or otherwise, arising from, out of or in connection with the material or the use or other dealings.

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

tags: common disease, orphan disease, orphan drugs, rare disease, disease genetics, cdc, epidemiology, sickle cell disease, sickle cell anemia, sickle cell anaemia, cdc, death certificate data, U.S. mortality tables, understanding death certificates, incidence of sickle cell disease, rate of sickle cell disease, cause of death, icd10, international classification of diseases

CDC Mortality Data: 7

This is the seventh in a series of posts on the CDC's (Centers for Disease Control and Prevention) public use mortality data sets. Yesterday, we introduced the concept of data mashups. The next several blogs will describe mashup techniques. For today's blog, let's focus on the kinds of biological questions that can be approached with the CDC data. You can't design a credible mashup until you've acquired some understanding of the potential value of the mashed up data.

Alpha-1 antitrypsin disease is a prototypical serpinase disease (disease due to deficiencies or abnormalities in the synthesis of serine proteinases). People with this disorder are homozygous for mutations in the alpha-1 antitrypsin gene. The full-blown disease is characterized by cirrhosis and emphysema. The pathogenesis of this diseases is somewhat complex, because there are a variety of different possible mutations of the gene, and the clinical manifestations vary somewhat with the mutation type. The cirrhosis is apparantly due to the intracellular accumulation of abnormal alpha-1 antitrypsin molecules within hepatocytes, and the emphysema is apparently the result of destructive effects of inflammation-induced intrapulmonary trypsin levels, unopposed by antitrypsin.

As is the case in most rare recessive genetic disorders, heterozygous mutations in the alpha-1 antitrypsin gene are found as common gene variants in the general population.

If a double-dose (homozygous) of an altered gene causes disease, what is the effect of a single (heterozygous) gene variant? Gene variations may be responsible for differences in the pathogenesis of disease among members of the apparently healthy public. About 15% of smokers develop COPD (chronic obstructive pulmonary disease) or emphysema. Why does one smoker develop COPD, while another smoker escapes pulmonary toxicity? Might the difference be accounted for by gene variations, and might a key gene be the alpha-1 antitrypsin gene?

A number of researchers have provided data indicating that heterozygous carriers of alpha-1 antitrypsin mutations are at increased risk for developing emphysema (Lieberman 1969 and Stevens 1971).

Lieberman, J.: Heterozygous and homozygous alpha-1-antitrypsin deficiency in patients with pulmonary emphysema. New Eng. J. Med. 281: 279-284, 1969.

Stevens, P. M.; Hnilica, V.; Johnson, P. C.; Bell, R. L.: Pathophysiology of hereditary emphysema. Ann. Intern. Med. 74: 672-680, 1971.

Population studies indicate that the African American population has much lower levels of alpha-1 antitrypsin disease gene variants than whites, the most prevalent mutations occurring in people with European ancestry (DeCroo 1991, Hutchison 1998).

DeCroo, S.; Kamboh, M. I.; Ferrell, R. E.:Population genetics of alpha-1-antitrypsin polymorphism in US whites, US blacks and African blacks. Hum. Hered. 41: 215-221, 1991.

Hutchison, D. C. S.: Alpha-1-antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z. Resp. Med. 92: 367-377, 1998.

We hypothesize that if alpha-1 antitrypsin disease mutations plays a significant contributory role role in the pathogenesis of emphysema in the general population, we can expect to see fewer emphysema cases in African-Americans (who are unlikely to be heterozygous for alpha-1 antitrypsin diseases mutations) than the white population. We can test this hypothesis by determining the percentage of African-Americans who die, in the U.S., with emphysema, and comparing that number with the percentage of White Americans who die with emphysema.

Here's the Perl script:

#/usr/local/bin/perl
open (ICD, "Mort99us.dat");
$line = " ";
while ($line ne "")
  {
  $line = <ICD>;
  $count++;
  $codesection = substr($line,161,140);
  $race = substr($line,59,2);
  $whitecount++ if ($race eq "01");
  $blackcount++ if ($race eq "02");
  if ($codesection =~ /J4[34]/)
    {
    $whiteemp++ if ($race eq "01");
    $blackemp++ if ($race eq "02");
    }
  }
close ICD;
$whiteempfrac = 100 * ($whiteemp / $whitecount);
$blackempfrac = 100 * ($blackemp / $blackcount);
print "Total records in file is $count\n";
print "Total African-Americans in file is $blackcount\n";
print "Total Whites in file is $whitecount\n";
print "Total African-Americans with emphysema $blackemp\n";
print "Total Whites with emphysema is $whiteemp\n";
print "Percent African-Americans with emphysema is ";
print substr($blackempfrac,0,4) . "\n";
print "Percent Whites with emphysema is ";
print substr($whiteempfrac,0,4) . "\n";
exit;

Here is the output from the script:

Total records in file is 2394872
Total African-Americans in file is 285276
Total Whites in file is 2064169
Total African-Americans with emphysema 15190
Total Whites with emphysema is 222996
Percent African-Americans with emphysema is 5.32
Percent Whites with emphysema is 10.8

The Perl script parses through the CDC mortality data for 1999.

Race is assigned a two digit code, 01 for White and 02 for Black, at bytes 60 and 61 of each record. The race code is pulled with the Perl statement:

$race = substr($line,59,2);

Emphysema and COPD cover ICD codes that begin with J4, followed by 3 or 4. Cases coded or emphysema or COPD are matched with the following Perl condition:

if ($codesection =~ /J4[34]/)

The Perl script examines 2.3 million death records in the CDC data set, informs us that African Americans have about half the rate of emphysema and COPD as does the White population. This observation is consistent with our hypothesis that the alpha-1 antitrypsin gene variant increases the risk of emphysema in the general population.

Does this observation prove the hypotheses? Absolutely not. The same observation could be explained by many different hypotheses. But we have shown, with a large number of cases (nearly a quarter million emphysema/COPD cases), that African-Americans have less disease than Whites.

This is the kind of analysis that uses existing CDC mortality data sets to develop and test a hypothesis. In the next few blogs, as we start to use CDC data in mashup applications, we will be developing hypotheses that relate our available data with informaiton that has a graphic representation (such as a map, or a physical drawing of a chromosome, or an anatomic picture).

© 2008 Jules Berman

As with all of my scripts, lists, web sites, and blog entries, the following disclaimer applies. This material is provided by its creator, Jules J. Berman, "as is", without warranty of any kind, expressed or implied, including but not limited to the warranties of merchantability, fitness for a particular purpose and noninfringement. in no event shall the author or copyright holder be liable for any claim, damages or other liability, whether in an action of contract, tort or otherwise, arising from, out of or in connection with the material or the use or other dealings.

---

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

tags: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, genetics of complex disease, genetics of common diseases, cryptic disease, cdc, epidemiology, neoplasms