January 26, 2009

More on reference ranges

I recently referred to an editorial in the Annals of Clinical Biochemistry that outlines ways to establish reference ranges and their attendant advantages and disadvantages. The authors of an editorial in January’s Clinical Chemistry (55:15-17, 2009) advocate “a new way of thinking about the relationship between biomarker measures and clinical decision-making?. They envisage the use of lab results to generate a prediction of risk of disease, which actually sounds a lot like existing likelihood ratios. These predictions will be based on data other than simply a lab measurement, for example, they might include the patient’s family and social histories, results of imaging studies, and even the patient’s desire for treatment. A result might be of the form that given the results of the lab studies, imaging, history etc. the patient has X% risk of having heart disease, cancer, etc. Certainly I agree with the assessment that traditional reference ranges have important limitations. To move beyond reference ranges to presenting the clinician with more useful data, specifically data that integrate findings from the history, physical exam, imaging, treatment desires etc. will take a lot of effort, much of which will be informatics related.

January 22, 2009

Testing in Pregnancy: Good Information from ACOG

The American College of Obstetrics and Gynecology (ACOG) has a nice brochure written for patients that gives a brief overview of many lab tests performed during pregnancy, including some we came across this week: hCG, blood glucose, urine protein, and STDs. It's well worthwhile taking a look at this pamphlet.

January 21, 2009

Common STDs in the United States

At this week's lab you will see an example of trichomonas vaginalis, a common protozoan STD. At the Tuesday lab, there was a good example of one of these organisms that was still very active with a clearly visible flagellum.

The CDC website has comprehensive data on surveillance for STDs (note that not all STDs are reportable). Among chlamydia trachomatis, neisseria gonorrhea, and syphilis, the first was the most commonly reported infection in 2007 with over 1.1. million new cases in the U.S., followed by gonhorrhea (355,000 cases) and syphilis (11,000 primary and secondary disease cases). By contrast, it's estimated that there are 8 million cases of trichomonas each year.

January 15, 2009

Subject-specific reference ranges

The reference range for many analytes, as mentioned previously, is commonly taken to be the middle 95% of values found in the population or in a stratified group based on age, gender, race etc. where these factors are known to influence the range of values found. The reference range depends on the intra-individual variation, the inter-individual variation, and the analytical imprecision. Unless the intra-individual variation is greater than the inter-individual variation, the reference range may be quite insensitive for detecting changes in a given subject. The formal comparison of these is known as the index of individuality, defined as the ratio of the CV(intra-individual)/CV(inter-individual). Values >1.4 suggest the reference range is sensitive for detecting changes in a subject, values <0.6 suggest it is not.

Maybe we should be paying more attention to intra-individual variation. A model for this is the study of hemoglobin concentrations in elite athletes. By regularly measuring their hemoglobin concentrations, it is possible to establish a subject-specific reference range that makes it easier to identify changes in hemoglobin concentration that may be associated with doping. A paper on this topic appeared some years ago.

January 14, 2009

Blood loss due to lab tests: use smaller tubes!

This week you are learning how to draw blood which is an important skill. In patients who require regular blood draws (such as ICU patients) the volumes of blood removed for lab testing can quickly add up. Often, the amount of blood that's drawn is far more than is needed to perform the lab tests. A recent article in Archives of Pathology and Laboratory Medicine reports the use of smaller blood collection tubes (pediatric size) for blood draws from adults. The results in hospitalized and intensive care patients are dramatic: reductions in volume of blood collected were in the 73-74% range. This kind of finding should encourage a review of whether smaller tubes can routinely replace larger collection tubes.

January 13, 2009

"What are you looking for in a Resident?"

On a recent Saturday morning our Department held its second and final session of interviews for the Laboratory Medicine and Pathology Residency program. The format is a change for us; we used to bring in applicants throughout the interview season (Fall-early new year) and each of us would meet with 2-3 of them on the interview days. Now we take 2 Saturday mornings when we bring in about 20 applicants and the faculty members individually meet with about 6. This format has some definite advantages for both the candidates and the faculty. For candidates, they get the benefit of a reduced airfare commonly associated with a Saturday night stay-over. They don't have to miss a full day of class. They get to meet their future colleagues in Pathology. We cover their Friday night stay in the hotel if they are from out of town, and provide breakfast and lunch on Saturday. For the faculty, it's a less hectic interview without the usual workday interruptions (phone calls, urgent lab issues etc.).

One of the questions I'm often asked by residency candidates is "what are you looking for in a resident?" It's a good question, and one that I thought I'd share here with this class of Medical Students.

The former head football coach for the Gophers, Lou Holtz, was looking for three characteristics in his players: ability, motivation, and attitude. This is similar to what I tell our resident applicants: I am looking for enthusiasm. Using Holtz's terminology, and thinking of the challenges that medical students have faced from kindergarten to getting into medical school, I take it as a given that you have learning ability, that is, the ability to study, acquire knowledge, and regurgitate it for exams. This ability is probably one of your fortes. I know less about your motivation although I assume it's also excellent, but I know practically nothing about your attitude, yet in the long run all three are critical to success. Of course, they overlap to one degree or another. A motivated student can improve his or her ability with intensive and focused effort. A good attitude is important for motivating oneself and one's teammates (and trust me, modern Medicine is a team activity). What I mean by enthusiasm encompasses something of all the characteristics that Holtz was looking for, but I am particularly interested in attitude.

Every resident applicant is required to write a personal statement. One that I will always remember from years ago was from a student who described how she, as a child, performed the autopsies on her neighborhood's dead pets! Her friends would come over with a dead guinea-pig, hamster, bird or whatever animal the Grim Reaper had visited, and her job was to figure out the cause of death. As I read her essay I thought she must be either really weird or had found her life's calling at an early age, but what came across very clearly was her enthusiasm. It's usually immediately obvious when I meet with a residency applicant that he or she is someone who is really interested and eager to learn.

Enthusiasm has a positive effect on most interviewers when they see it because it's such a differentiator in a group that already has proven academic ability and motivation. And beyond just interviews, enthusiasm is what most of us hope to find in the people we work with. At least it's what I'm looking for.

[First posted Dec 31, 2007]

January 12, 2009

Pre-employment testing for chronic diseases?

My friend and colleague, Dr. Bruce Friedman, in a blog post last week mused on whether pre-employment testing for chronic diseases was legal. It's an interesting question because so many chronic diseases such as diabetes, or risk of heart disease are identifiable merely by doing laboratory testing. According to an article in HR Magazine from 1992 the Americans with Disabilities Act (ADA) specifies that:

...after making a conditional offer of employment, but before the applicant actually commences active employment, an employer may make unrestricted medical inquiries, but may not refuse to hire an applicant with a disability based on the results of such inquiries, unless the reason for the rejection is "job-related and justified by business necessity."

This makes me wonder what, if any, duty an employer who discovers some medical information about a job applicant has to disclose that information to the applicant (particularly if the applicant is not hired)?

The more recent Genetic Information Nondiscrimination Act of 2008 prohibits the use of an individual's genetic information for making hiring or firing decisions. An article in the New England Journal of Medicine last year outlines the provisions of that act.

Rainbow Drawing

I first came across the term "rainbow draw" quite recently. It refers to the practice of drawing one of each blood tube type from a patient without a clear understanding of which tests are going to be performed. Some tubes have anticoagulants, of which there are there are several types (e.g., heparin, EDTA, citrate), some have serum separator gels, some are just plain tubes and so on. These tubes are recognizable by the different color of their caps and so the allusion to a rainbow. We use different tubes because some assays require serum (e.g., chemistry tests), some require anticoagulated blood (e.g., complete blood counts), some require plasma (e.g., coagulation assays) and so on.

A rainbow draw is a strange approach to sample collection! Some of these tubes are quite specialized, and it's unlikely most patients would routinely need, for example, a tube collected for analysis of heavy metals. I understand that having to re-draw a patient is time consuming and perhaps uncomfortable for the patient, but drawing one of every tube is a waste of tubes, a waste of blood, and a substitute for rational thinking about which tubes are needed for different laboratory tests.


January 9, 2009

Newborn screening stories from the MN Dept. of Health

During the Introductory lecture, we talked about newborn screening programs as an example of an indication for performing a laboratory test: identifying disease in people who don't have any symptoms or signs other than what can be discovered by laboratory analysis.

The Minnesota Dept. of Health has recently included some individual patient stories on the website for the state's newborn screening program (I am a member of the advisory panel for the newborn screening program). These stories, told by parents or children who might have died or been very ill had it not been for early recognition of their disease, bring out very powerfully how important this program and others like it are to these families.

January 8, 2009

Reference Ranges

This week we are looking at reference ranges and how they are established. An interesting editorial on this topic can be found in the January edition of the Annals of Clinical Biochemistry (46) 1-2, 2009, which also includes a couple of interesting papers on the approaches using "healthy" populations and real patient data. The editorial writer comments on these various approaches to defining reference ranges:

1. A classic based approach is to draw samples from a well defined cohort(s) of healthy people and typically take the middle 95% of values (mean +/-2 SD). This is required if there are variations between people of different age, gender, race etc. There are limitations to this approach: Who is healthy? Should there be a separate reference range for symptomatic people? How do we define ethnicity in populations that are composed of people of mixed ethnicity? For how long are samples stable prior to analysis?

2. The use of patient data to establish reference ranges. This may seem at first sight to be an odd way to establish a reference range. Almost by definition, patients have some health problems. On the other hand, many patients do in fact have concentrations of many analytes that are within the ranges found in healthy people. If one excludes the "outlier" values, it is possible to derive a reference range that at least approximates that seen in healthy individuals. The other objection to the use of patient samples is that there may be pre-analytical variation that is not seen in carefully collected samples used solely for the purpose of establishing a reference range. The answer to this objection is that "real" patient samples are usually drawn and transported under less than ideal conditions. If there is variation seen because of pre-analytic factors, then shouldn't it be reflected in the reference range?
A big advantage of using real patient data is that large numbers of data points are available and, importantly, from groups such as children, from whom it is generally extremely difficult to get samples to do a reference range study.

So we have a "purist" approach and a "pragmatist" approach to reference range establishment. (Yes, Laboratory Medicine has its own set of disputes!) Moreover, those are not the only ways to think about lab values that require a clinical response. Some people advocate Decision Limits. In a nutshell, these are values that trigger a clinical decision (e.g., a diagnosis or a therapeutic intervention). We talked about some of these in the context of cholesterol and glucose, and how those values that have clinical significance are not evident from a simple statistical analysis of the distribution of values in health or disease. These are what I refer to as a "reference range by committee".

When it comes to reference ranges, all of these different approaches need to be considered; there is no one approach that is clearly right or wrong in all circumstances.

January 7, 2009

Blood utilization in the U.S. vs. other countries

I spent most of today at a conference to look at ways to improve blood utilization. This refers to efforts to reduce the rates of transfusion of blood products to patients for whom these products are ordered for a variety of reasons. In our case, we are one of the largest users of platelets in the country because of the active and large bone marrow transplant program.

There was a very good representation of physicians, nurses, laboratory staff, perfusionists, pharmacists, quality improvement staff and administration at the conference and there was a lot of enthusiasm about making changes that could reduce utilization while maintaining quality and patient safety. The external consultants, Strategic Healthcare Group from Indianapolis led by Dr. Tim Hannon, organized the discussion.

One of the interesting snippets of information that came out has to do with relative utilization of blood products in the U.S. vs. other countries. To quote from "The Bloody Truth", a listing of some talking points from Strategic Healthcare :

Blood utilization in the United States is significantly higher than in most Western countries and the gap is increasing. While blood utilization in the U.S. increased by 16% from 1999-2004, it decreased by 8% in the United Kingdom during the same period. Remarkably, blood utilization in the U.S. is currently 15% higher per capita than in Europe and 44% higher than in Canada. This difference is likely attributable to a combination of higher blood prices, national transfusion education progams, hemovigilance programs which spotlight transfusion risks, and accountability for performance and compliance at the hospital level.

Of course, the same could be said for many aspects of medical care in the United States. I see this as a manifestation of a "culture of abundance", which means that we enjoy vast resources, perhaps unparalleled in many other parts of the world. The question is do we always use these resources judiciously and prudently? Is more always better? When it comes to blood products, the answer is clearly, 'no'. There are risks associated with transfusion of blood, and the goal should be to transfuse what's needed for an individual patient, and no more.

January 5, 2009

CAP Survey: Seventy percent of clinical labs in U.S. reporting eGFR

The number of clinical laboratories in the United States that report estimated glomerular filtration rate (eGFR) is now 70% according to recent data from the College of American Pathologists. These data are derived from laboratories that participate in the College's proficiency testing program and so tend to be larger labs such a reference labs and hospital labs. This is good news. Chronic kidney disease is a major public health problem and we will be looking at this in more detail later in the course.

There are two ways to screen for CKD: estimated glomerular filtration rate based on serum or plasma creatinine as calculated using the Modification of Diet in Renal Disease (MDRD) formula, and detection of albumin loss in urine. We will be looking at the specifics of these approaches when we come to renal function testing in a few weeks. The point to be understood now is that clinical labs are asked, where feasible, to routinely report the eGFR when creatinine is ordered. The idea of a reference range, which we'll be discussing this week, has to be re-examined for plasma creatinine because levels are so dependent on age, gender, and racial background. The MDRD equation is a way to move beyond the simple idea of a reference range (a one-size-fits-all approach) to getting a value that is appropriate to the individual patient and identifying those who have early impairment of renal function and who could benefit from therapeutic intervention.

January 1, 2009

Donald Gleason, M.D., Ph.D.

Dr. Donald Gleason, a former pathologist at the Minneapolis VA Medical Center and faculty member at the University of Minnesota died a few days ago. His obituary is in today's Minneapolis Star Tribune (link). Dr. Gleason was the man behind the prostate cancer grading system that bears his name. It is used throughout the world today. I had the privilege of meeting Dr. Gleason last year when he received an award from the Minnesota Society of Pathologists. His contribution to medicine was enormous.

December 30, 2008

CYP2C19 and Clopidogrel Efficacy

A series of articles in the New England Journal of Medicine and the Lancet this week report on the clinical impact of deficiency alleles of CYP2C19. This cytochrome P450 is required for activation of the anti-platelet drug, clopidogrel. Deficiency alleles are common in the population and result in decreased activity of the P450 enzyme. Subjects who carried a deficiency allele(s) in these studies had worse clinical outcomes than did subjects with functional alleles. These findings make the case (again) that drug dosing often needs to be tailored to account for genetic differences between patients. We are used to thinking about genetic factors in the susceptibility to and causation of disease. Now we must increasingly think about them in a therapeutic context as well. Depending on the drug, some patients may need a lower or higher dose. In some patients, a drug may have no benefit or be highly toxic. The key is to make this determination in a timely way so that patients receive maximum benefit with minimum risk. Ideally, we would link results from laboratory genetic analysis with data on the likely phenotypic consequences and present this information in a useful way to the clinician at the "sweet spot", that is when a decision about choosing a drug or dosage is being made.

December 12, 2008

Welcome to the Course!

Welcome to the Laboratory Medicine Course!

In this course, we will be introducing you to the clinical laboratory and providing you with practical exposure to some lab procedures that you will use frequently in your future medical practices. As with most courses, you get out of it in proportion to what you invest in it. You should attend all of the laboratory sessions and read the text. Many of the Course materials will be accessible at the Course website (built in Moodle) and accessible for registered students through myu.umn.edu.

The clinical laboratory plays a central role in modern health care. It has been estimated that at least two-thirds of all diagnoses rely to some extent on a laboratory finding. The clinical laboratories at the University of Minnesota Medical Center, Fairview, cover numerous sub-disciplines including clinical chemistry, microbiology, hematology, coagulation, blood banking, molecular and cytogenetics, and tissue typing. The professional field that is responsible for medical directorship of all of these areas is known as Clinical Pathology (sometimes called Laboratory Medicine or "CP"). In the organization of Pathology, the major fields are Anatomic Pathology ("AP") and Clinical Pathology.

Clinical Pathology at Minnesota
You might have noticed that our department has a double-barreled name, “Laboratory Medicine and Pathology". Originally those were two separate departments, with Laboratory Medicine being an offshoot of Internal Medicine, and one of the first such departments in the country. For the last few decades, these have been a unified department that covers all clinical laboratory testing at this medical center. We also serve as a reference laboratory for numerous physician office and hospital clients both in Minnesota and out-of-state. Our department is a highly rated academic department and our laboratories are known for their excellence. Please feel like you’re a member of our department during your course, and at any time, feel free to contact me or the Course Coordinator, Mary Ramey, with any questions or concerns.

Anthony A. Killeen, MD, PhD, FCAP
Associate Professor
Director of Clinical Pathology
Course Director

X.500: kille001