Life Extension Magazine®

Issue: Oct 2003

Laboratory Test Analysis Alters Course of Life

Today’s scientific breakthroughs and unprecedented medical resources are rarely delivered in a timely fashion to the patient’s bedside. Learn how patients and physicians alike can employ the basic concepts and principles of laboratory testing to prevent illness, diagnose disease earlier and achieve better treatment outcomes.

The Importance of a Medical Detective Mindset to Achieve an Early Diagnosis, Proper Evaluation and Successful Treatment
By Stephen B. Strum, M.D., Medical Oncologist Specializing in Prostate Cancer

Editor’s Note: While this article may be somewhat technical for the average reader, it contains innovative, life-saving medical concepts that should be shared with your doctor. For this reason, we are publishing it in an attempt to improve the way that medicine is practiced. Ideally, doctors will integrate these critical procedures into their practice and “you as patients will be better served.”

In today’s world of major scientific breakthroughs we are often left wondering why high-tech achievements are not incorporated into the everyday care of the patient. So called translational medicine—that is supposed to bring to the bedside that which we have learned at the bench (research laboratory)—is just not happening. Added to this is the medical profession’s failure to use the tools currently available to almost every practitioner. Therefore, as patients and consumers within the health industry, our protest should be not only that we are not benefiting in a timely fashion from the new advances in medicine made in the research laboratory, but also that given the proverbial tool bag of medical resources presently available, alas, many of these tools are not used at all.

The following article presents to the reader concepts that are critical to our lives. Although the main focus is on laboratory testing, the same principles apply exactly to radiology and pathology, as well as to the findings of the history and physical examination. We have had the tools to employ concepts to prevent illness, to diagnose disease earlier and to achieve better treatment outcomes for many years, but they are not as widely nor as universally used as they should be. The tools described here are not expensive and are not elusive to the empowered patient and the caring and conscientious physician.

I. Biologic Indicators, Medical Profiling and Concordance.
When it comes to an appraisal of our health status, we routinely rely on biologic indicators. Such indicators are “biologic LEDs”—just like the “light emitting diode” readout indicators on your automobile’s dashboard. These biologic markers are called biomarkers because they relate information about life forms. They represent biofeedback from a myriad of mind-body interactions. When a physician evaluates a patient, he takes a history and performs a physical examination. These are inputs into the medical detective (MD) framework that a true physician uses as part of his mode of operation (MO or modus operandi). Beyond the history and physical, a physician samples the patient’s biology by ordering the appropriate laboratory, radiology and/or pathology examinations. He obtains a profile that more comprehensively relates the status of a particular tissue, organ or system within the body. This is medical profiling, and at its best it facilitates early diagnosis and timely treatment. A good detective, however, does not rely only on one piece of circumstantial evidence to solve the mystery. He obtains corroborative evidence to confirm and support his initial premises. Similarly, medical profiling at an optimal level involves additional studies that either confirm or refute the significance of the initial observation. If two or more findings point to the same conclusion, a condition known as concordance is met. Concordant findings increase the statistical significance in the course of diagnosis, staging of disease, prognosis and outcome of treatment.[1-3] Figure 1 attempts to depict the steps involved in this initial data acquisition and processing (IDAP).

Figure 1: Initial Data Acquisition and Processing (IDAP): The Importance of Medical Profiling and Concordance.
Medical investigation at its highest level involves obtaining biologic inputs from the various systems of the human mind and body. These biologic inputs are used to create a medical profile. The accuracy of such an investigation increases if additional evidence indicates that there is agreement or concordance with the initial observation. Example: A 65-year-old man with a history of diabetes in his family complains of frequent urination. His urinalysis reveals the presence of protein and glucose. A fasting blood sugar is obtained and is 150. A glycohemoglobin (hemoglobin A1C) level is drawn and is elevated at 7.9. The patient is diagnosed with diabetes mellitus and an appropriate treatment strategy ensues. Here, initial inputs of information led to a tentative diagnosis of diabetes and additional test results were concordant with this diagnosis.

II. Validation, Response Parameters and Stratification
An important aspect of accurate data analysis is the quality of the data obtained. There may be significant variability in the accuracy of the biologic inputs we obtain. A biologic indicator is only good if it reflects the true status of the patient. The old saying is “garbage in equals garbage out.” This is somewhat blunt but it does find its reality in the variable skills involved in medical evaluation that lead to issues of false positive or false negative findings. This can relate to variations in proficiency of a laboratory or radiology imaging center or to the skill of a medical examiner or a pathologist interpreting a biopsy or surgical specimen. To minimize this pitfall within the methodology of medical profiling, a simple measure known as validation should be used. Validation results in a higher level of confidence that the finding or diagnosis being made is a correct one. For example, repeating an abnormal laboratory or radiology finding or obtaining a second pathology opinion from a recognized expert involves validation.

Once we have obtained validated biologic inputs, and hopefully have substantiated their importance through the concept of concordance, we now have a high-level medical profile not only to diagnose an illness earlier, but also to optimize a treatment strategy. If we have come this far as a “medical Columbo” then the use of response parameters logically follows. Response parameters are the gauges we use to determine objectively if the selected therapy is achieving its goal. For example, on a very elementary level, if within the process of medical profiling we determine that a patient has obesity and diabetes, we should at least select the response parameters of body weight, blood sugar and hemoglobin A1c to follow up on the condition of the patient in order to ascertain whether our therapy is effective. It is amazing to see how many patients with medical problems such as obesity and diabetes do not have these issues addressed despite having been placed on a formal medical therapy. Many of these same patients do not have the desired therapeutic response and continue to suffer the consequences of these medical conditions. To add insult to injury, many may also experience adverse effects that lead to morbidity and mortality. In a study reported in 1998, adverse drug reactions in the United States in 1994 were among the top ten leading causes of death, accounting for 106,000 fatalities,* not to mention an additional 2,216,000 serious adverse drug reactions.†[4] Thus, not only do we need to recognize the value of biologic indicators and of medical profiling and its subtleties, but also to acknowledge that we must use biologic endpoints to objectively grade our treatments. The proof of the pudding is in the eating.

* 95% confidence interval 76,000-137,000
† 95% confidence interval 172,000-2,711,000

In its highest form, medical profiling also invokes the process called stratification. In this course of action, we first obtain the patient’s biologic data via the processes of profiling, concordance and validation. Then, a determination is made to place the patient into high, intermediate or low risk categories involving organ systems vital to health. These include the cardiovascular, pulmonary, hepato-biliary, renal, gastrointestinal, male or female genitourinary, nervous system, skeletal system, endocrine, immune and cutaneous systems. This concept may be applied to situations that involve family history and the risk of a specific illness. It also should be used in situations where a diagnosis has been established and a grading of the apparent severity of the illness, i.e., stratification, has relevance to the nature of the treatment, its prognosis and its outcome.

Organization: What a Concept!
After 40 years in medicine involving consultation with thousands of patients from all over the United States and abroad, it is evident to me that we are not employing the above concepts. This is blatantly the case when it comes to utilizing the wealth of resources coming from the laboratory. Within the context of laboratory testing, a lab result is not just a report that is added to a manila folder that relates “normal” versus “abnormal.” Rather, it is a biologic indicator that reflects the status of our health in a dynamic fashion.

Unfortunately, what most often happens when lab tests are ordered is that the reports are put into the doctor’s inbox along with a morass of other paperwork. The doctor “eyeballs” the reports, looking to spot what might represent any abnormal finding. Often, the physician has not initialed the report to acknowledge that he has reviewed it and ideally that he has given more than a glancing thought to it. The report is then filed in the patient’s chart. Too often the “medical record” is a manila folder with assorted test results and other documents thrown together. There is no organization of data by category (i.e., laboratory, radiology, cardiology, pathology, consultations, office visits, correspondence and even routine physical exam assessments like weight and blood pressure) or by chronology, with sorting of oldest to newest data within the above categories.

How Laboratory Test Analysis Alters the Course of Life
The Importance of a Medical Detective Mindset to Achieve an Early Diagnosis, Proper Evaluation and Successful Treatment
By Stephen B. Strum, M.D., Medical Oncologist Specializing in Prostate Cancer

What is “Normal?”
The biologic LEDs referred to above are indicators of cellular function or dysfunction. These biomarkers usually are obtained from the patient’s blood or urine and are ascribed a range or span which is considered “normal.” Unless we know what the patient’s baseline is and track test results over time, we have no idea if the status of the patient’s tissue or organ is stable, improving or worsening. In other words, the essence of biomarker analysis involves the tracking of a laboratory test(s) over time. When this is done for purposes of appraising the status of a tissue, organ or body system, then we increase our ability to optimize health outcomes.

Returning to our analogy with the automobile, we check the oil level with a dipstick or gauge. Using the results of our baseline measurement, we know if the level is dropping lower. We also obtain a sense of how rapidly the level may be dropping if assessments are being made at periodic intervals. Both inputs—the absolute level and the rate of change—affect our response to this situation. This use of chronology incorporates the important considerations of baseline value plus subsequent testing over the dimension of time. This is critical in the appraisal of dynamic biologic systems involving all life forms. A few examples are appropriate at this time.

A Clinical Vignette
A former employee of mine tearfully asked me to help evaluate her mother’s condition. Her mother (LT) had just been diagnosed with stomach cancer. At the time of her diagnosis, she was already jaundiced due to extensive metastases to the liver. LT was also anemic because the primary stomach cancer had eroded the gastric wall causing bleeding into the gastrointestinal tract. I obtained all of the patient’s medical records, which included those from years before her diagnosis so that I could get a true sense of the pace of what now appeared to be fulminant disease. In assessing LT’s anemia, the results of past CBC (complete blood count) tests were reviewed. The CBC includes the white cell count, hemoglobin, hematocrit and the platelet count. It also includes other measurements such as the mean cell hemoglobin concentration (MCHC) of the red blood cell as well as the size of the red blood cell (mean cell volume or MCV). I found a baseline hematocrit of 45% obtained three years before the diagnosis. Sorting all the medical records chronologically, I could track the fall of the hematocrit to the low 40s, and from there into the 37% to 39% range, and then eventually to her severely anemic value of 31% (Figure 2).

Hematocrit Over Time
Figure 2: The Importance of Baseline and Chronology in Assessing Laboratory Results.
The change in a biologic input over time provides a superior perspective about any alteration in biologic function. The hematocrit is a highly stable biomarker and a fall in value from a stable baseline of 45% to 42% would justify repeating the study. The drop to 37% should have prompted a major clinical investigation to determine the cause of anemia.

In addition, the mean cell volume (MCV) had progressively dropped over time from 88 to 85, to 78 and then to 74 at the time of diagnosis. Values of less than 80 should be an alert to iron deficiency anemia. A trend indicating falling values, even though still within the range of “normal,” should be a red alert to an astute M.D. Causes of iron deficiency anemia to be considered would include blood loss due to ulcer disease in the stomach or duodenum, malignancy anywhere in the gastrointestinal tract, hiatal hernia with or without esophagitis, helicobacter pylori gastritis, celiac sprue and atrophic gastritis.[5,6] In LT’s case, regardless of the cause of her abnormal blood picture, her illness had declared itself through changing laboratory findings years before any clinical symptoms. The M.D. (medical detective) had not discerned this. Instead of an early diagnosis for LT, she was diagnosed with far-advanced stomach cancer with extensive liver metastases. Her condition was so weakened by her advanced presentation that anti-cancer therapy was compromised. She died within a few months of her diagnosis.

If a proper assessment of LT’s lab results had been done as part of her medical assessment, her diagnosis of stomach cancer would have been made years earlier, perhaps when the cancer was still localized to the stomach and before it had a chance to metastasize to the liver. A similar assessment of the liver status also revealed that the level of alkaline phosphatase had been slowly and steadily climbing—even within the so-called “normal” range. Unfortunately, no note was made of this until the result rose beyond the upper limit of normal and then entered into “abnormal” territory. When the patient was finally diagnosed, her liver was so extensively involved with cancer that she was already jaundiced. Physicians and patients must both realize that biologic indicators don’t go from normal to abnormal as though a light switch were turned from “off” to “on.” These biomarkers declare themselves more in the manner of a dimmer switch that raises the level of light progressively. More often than not, changes in biomarker levels are apparent on retrospective review for years before the pathologic condition has become blatant. Thus, the change over time or trend is a critical concept in biologic systems that mandates attention.

Evaluating Laboratory Dynamics Adds to Baseline and Trend Strategies
A second and fortunately less dramatic case history involved a 54-year-old patient (RK) with a diagnosis of prostate cancer made in June 2003. He had a family history of prostate cancer (PC) involving his father and one of his three brothers. He was therefore stratified as a high-risk patient due to family history that indicated he had hereditary prostate cancer (HPC).[7-9]

Because of this, RK had diligently obtained PSA (Prostate Specific Antigen) values every year starting at the age of 40. His baseline PSA was 0.6 ng/ml. Over the course of the next 10 years, the PSA had slowly climbed to 1.0. At age 51, the PSA was 1.4 and shortly after RK’s 52nd birthday it had risen to 2.0. His family physician assured RK that this was still well within the “normal” range for PSA (1.0-4.0 ng/ml). A year later the PSA was 2.5 and at age 54 it had risen to 4.4. This prompted RK to seek a further opinion with a urologist who ordered a free PSA percentage, which came back as 6.8%. This result was highly worrisome for the presence of prostate cancer. Using the data inputs of RK’s age, total PSA and free PSA values, his probability of having PC was 87%.[10] A transrectal ultrasound of the prostate with 12 biopsy cores was performed and confirmed a diagnosis of PC with a Gleason score of (4,4) involving 6 of the 12 cores. (A Gleason score is a method for classifying the cellular differentiation of cancerous tissues. High numbers indicate the presence of cancer.) He was advised to have a radical prostatectomy (RP), which was performed in July 2003. The specimens obtained at the time of RP revealed PC with involvement of two pelvic lymph nodes.

RK and his family were upset. Why was the diagnosis of PC not made earlier?

A more scientific analysis of RK’s biologic LEDs might have led to an earlier diagnosis. In the case of prostate cancer, the PSA values are the markers to watch. Inspecting the PSA values with a focus on the actual rate of increase of the PSA over time suggested that his biologic system was in disarray and needed more attention. In other words, besides looking at an absolute value of a PSA determination, or even viewing the changes in values over time, more objective and more comprehensive evidence is obtainable. Such determinations reflect laboratory dynamics. In this case, it involves a derivative of PSA testing called PSA velocity or PSAV. This provides more cogent information on the status of the patient’s prostate gland. The PSAV relates information about the increase in PSA in the blood over time (acceleration) using the measurement of nanograms (ng) per milliliter(ml) per year(yr). The medical literature has established that a PSAV of 0.75 ng/ml/yr or higher is an indicator of high risk for the presence of PC.[11-15] Therefore, RK’s biologic LEDs suggested the presence of a “malfunction,” but this was missed because the focus of the M.D. was on an absolute value, and not laboratory dynamics such as the acceleration of the PSA, i.e., the PSAV.

Using Combined Variable Analysis Further Enhances Medical Detective Work
When it comes to understanding biologic systems in the context of laboratory evaluation or other diagnostics, the importance of substantiating data inputs, i.e., additional variables of information, must be stressed. Finding multiple variables of information suggesting a malfunction adds further circumstantial evidence that increases the accuracy of diagnosis. This is incorporated in the concept of combined variable analysis and it applies to all analytic data. In the context of PSA dynamics, additional variables of information might also include:

  • PSA doubling time (PSADT)
  • Free PSA percentage and its derivatives:
    • Free PSA percentage velocity
    • Free PSA slope
    • Free PSA doubling time and related inputs
  • PSA density (ratio of PSA to the prostate gland volume)
  • Free PSA density

When we review a patient’s biologic LEDs in this manner, we elevate our analysis and enhance our ability to provide the patient with an early warning system. In the case of RK, this was done retrospectively. The PSA doubling times are shown in Table 1. The average PSA doubling time for prostate cancer at the time of diagnosis is approximately 24 months. Conditions such as benign prostate hyperplasia (BPH) usually have PSADT’s of more than 12 years (144 months). Healthy prostate tissue, in contrast, has a PSA doubling time as long as 54 ± 13 years.[16] RK had a PSADT of about two years as far back as May of 2000, three years before his diagnosis was established.

Date PSA
ng/ml
PSA velocity
(PSAV) ng/ml/year
PSA doubling time
(PSADT) (mos)
Free PSA
percentage
Free PSA
halving time (mos)
May 1997 0.8 - - 48%  
May 1999 1.0 0.1 74.35 40% 90.99
May 2000 1.4 0.399 24.72 25% 17.70
June 2001 2.0 0.553 25.23 18% 25.25
May 2002 2.8 0.874 22.56 12% 20.46
June 2003 4.4 1.475 19.91 6.8% 14.60
Table 1: The Use of Laboratory Test Derivatives Enhances Diagnostic and Prognostic Ability.
In the case of RK, despite so-called normal PSA values of less than 4.0 ng/ml, his PSAV, PSADT, and free PSA percentages all were consistent with a diagnosis of prostate cancer. The halving times relating to the free PSA percentages, though not a test currently in use, have relevance to the diagnosis and prognosis of prostate cancer.

The free PSA percentage test reflects that PSA comprises two major subunits of PSA: the free PSA and the complexed PSA. The complexed PSA is associated with prostate cancer; the free PSA is not. The higher the free PSA%, the less likely that the patient has prostate cancer. The lower the free PSA%, the more likely that there is more complexed PSA and the presence of PC. The serum from RK’s past lab tests had been frozen and stored in the laboratory. These specimens were obtained and free PSA percentages were determined. Table 1 shows that in May 1997 free PSA was 48%; in May 1999 it was 40%; and in May 2000 it was determined to be 25%, and with each passing year it dropped lower and lower.

The concept of using the derivatives of a specific test to understand dynamics of biologic testing can be applied to any biologic LED. And because biologic events represent living, metabolizing and sometimes growing biologic entities, it is entirely reasonable that such dynamics are of major importance.

Others have taken this approach when it comes to using the free PSA percentage to determine PSA density.[17] In the case of RK, instead of PSA doubling times, free PSA percentage halving times were calculated from 1997 to 2003. Although such calculations and their interpretations have yet to be published in the medical literature, it was clear that an inexorable fall in free PSA percentage started after 1997. This was expressed in the approximate halving times of 91, 18, 25, 20 and 15 months relating to the respective time periods of 1997-1999, 1999-2000, 2000-2001, 2001-2002 and 2002-2003. In other words, the malignant condition was expressing itself with shorter and shorter halving times of the free PSA percentage. This was a biologic expression of a growing malignancy consisting of prostate cancer cells making more and more complexed PSA and therefore dropping the free PSA percentage lower.

How Laboratory Test Analysis Alters the Course of Life
The Importance of a Medical Detective Mindset to Achieve an Early Diagnosis, Proper Evaluation and Successful Treatment
By Stephen B. Strum, M.D., Medical Oncologist Specializing in Prostate Cancer

A Practical Application of the Above Concepts
All of the above serves little or no purpose if we cannot elevate the utilization of what we garner from testing biological systems. It gets back to the issue of translational medicine. The proof of the pudding when it comes to the laboratory is not just the eating, but also the assimilation of information and its utilization. How then, can the empowered patient utilize what has been discussed in the foregoing sections regarding laboratory testing?

1. Take Advantage of Biomarkers
Understand that your body and mind sends out millions of signals every moment. These are more or less specific to body systems but are clearly interlinked in truly integrative circuits (upper portion of Figure 1). At the present time, we have an expanding repertoire of laboratory and other markers of biologic activity involving history and physical examination, pathology testing and radiologic studies. If these are available to you, then use them.

2. Confirm a Medical Problem with Concordant Testing
If you appear to have a particular diagnosis or a change in the status of an existing illness, investigate to see if there are corroborating tests available. Enhance the accuracy of any clinical evaluation by using the principle of concordance. If it looks like a zebra, sounds like a zebra, has stripes and four legs, and runs like a zebra, it is probably a zebra.

3. Validate Critical Laboratory Test Results
If your medical situation is such that you are at a juncture that is possibly critical, then repeat any result that comes back abnormal or different from a previous result. This confirmation process may require you to obtain a third value as a “tie-breaker.” Use your common sense to ascertain whether you have a situation that appears to be going from good to worse. If the laboratory interpretation requires the expertise of a recognized expert, obtain such consultation. Search for the people of special talent. Don’t ignore signals from the body or mind. Listen to your biology!

Table 2: The Flow Sheet. The flow sheet uses the dimension of TIME to show how treatment or simply observation may be affecting a biomarker (response parameter). The front of the flow sheet is focused on the laboratory parameters. This is done in the context of also listing the patient’s current medications and their doses in order to determine if any laboratory result is being affected by a treatment or therapy. Using the flow sheet improves the quality of the physician’s care of the patient. Trends are easily seen and adverse effects due to therapy are easily noted.

4. Plot Your Lab Results to Determine a Trend Line
Use the dimension of time to investigate the significance of a finding. If a test result is changing, pay attention. “Abnormal” rarely happens suddenly; it develops over time. Look for physicians who present data in a graphic format.[18,19] If you cannot find such a service, then use your own mathematical and/or computer skills to create a spreadsheet, graph or other tool to visually portray what is happening to your biomarkers. One such tool that is able to fulfill some of these objectives is a simple form called a flow sheet (Table 2). The flow sheet, used properly, objectifies and emphasizes the concepts of trends over time and response parameters. It accomplishes this by showing correlations between treatments of any kind (medications, surgery, radiation) and laboratory, radiology, physical examination findings; it does this in the context of results depicted over time. Flow sheets should be a mandatory part of every physician’s chart work. They can be tailored specifically to the patient’s unique medical issues.

5. Use Biomarkers as Response Parameters (Biologic Endpoints)
If you are being treated for iron deficiency anemia, then use endpoints like hematocrit, MCV, serum ferritin and possibly soluble transferrin receptor assay as means to determine the success or failure of a therapy.[19-21]

If you have been diagnosed with osteopenia or osteoporosis, you may receive treatment with oral bisphosphonate medications such as Fosamax® or Actonel®, or intravenous bisphosphonates such as Aredia® or Zometa® to stop bone loss (bone resorption) and reverse osteoporosis. Such medications work by inhibiting the osteoclasts that break down bone. If anti-resorptive therapy has been successful, then a decrease in the metabolic breakdown products of the bone found in the urine will be confirmed. The latter test is called Pyrilinks-D or free deoxypyridinoline (Dpd). It is all too common to see patients taking bisphosphonates for many months or years without any testing to see if a key biologic endpoint of bone resorption has been altered. “If it’s broke, see if it is being fixed.” Some patients taking bisphosphonates do not absorb these agents well and may need dose modification or some other type of therapeutic change. Don’t waste a year or more of time and money without knowing if you are headed in the right direction.

6. Use Combined Variable Analysis
When biologic inputs, each with independent statistical significance, are used together, they present a more powerful tool that may enhance the accuracy of diagnosis, staging, treatment assessment and prognosis, as well as prevention. In such a scenario, the total is greater than the sum of its parts. This is the essence of combined variable analysis—a landmark concept linked with the previously discussed concepts of medical profiling and concordance.[22-28] Combined variable analysis presents the patient’s biology within the framework of the medical histories of thousands of patients who have presented in a fashion similar to the patient under study. This is medical history. Patients, partners and their physicians must learn the lessons that such history teaches us, or regrettably, the patient is forced to repeat it.

The majority of patients that utilize the above approaches have realized the significance of the preceding concepts. It’s your life—take the very best care of it!

Biography of Stephen B. Strum, M.D.
Dr. Strum has been a board-certified medical oncologist since 1975. In 2000 he became the first medical director of the PCRI (Prostate Cancer Research Institute) in Los Angeles. Dr. Strum has published widely about prostate cancer as well as other areas to optimize the outcome for those faced with the challenge of having cancer.

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