The spurious correlation between concentration and creatinine-corrected concentration in urine

Simon Brown, Delwyn G. Cooke, Leonard F. Blackwell, David C. Simcock


The use of urinary analytes to monitor physiological processes relies on making the correct measurement.  Three alternatives are commonly contemplated: concentration, creatinine-corrected concentration and excretion rate.  Of these, the latter is the most reliable, but is perceived by some to be difficult to measure.  This has led to the more frequent reliance on concentration and one of the justifications for this is the reported linear relationship between the concentration and the creatinine-corrected concentration.  We show that this correlation is spurious in that the magnitude of the correlation coefficient depends on the ratio of the standard deviations of the creatinine and analyte concentrations.  As an example urinary analyte we use pregnanediol (Pd) which is an important tool for women wishing to monitor their own fertility.  Urinary Pd concentration is not a reliable substitute for creatinine-corrected Pd concentration or the Pd excretion rate.

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H. Adlercreutz, O. Jänne, T. Laatikainen, B. Lindstrom, T. Luukkainen, and R. Vihko, "Studies on conjugated mono- and dihydroxy metabolites of progesterone in plasma, bile and urine in a human subject," Bulletin der Schweizerischen Akademie der Medizinischen, vol. 25, pp. 328-336, 1969.

H. C. M. Allaway, N. I. Williams, R. J. Mallinson, K. Koehler, and M. J. de Souta, "Reductions in urinary collection frequency for assessment of reproductive hormones provide physiologically representative exposure and mean concentrations when compared with daily collection," American Journal of Human Biology, vol. 27, pp. 358-371, 2015.

M. E. Alliende, J. A. Arraztoa, U. Guajardo, and F. Mellado, "Towards the clinical evaluation of the luteal phase in fertile women: a preliminary study of normative urinary hormone profiles," Frontiers in Public Health, vol. 6, pp. 147, 2018.

W. R. Atchley, C. T. Gaskins, and D. Anderson, "Statistical properties of ratios. I. Empirical results," Systematic Zoology, vol. 25, pp. 137-148, 1976.

T. S. Baker, K. Jennison, and A. E. Kellie, "A possible method for the detection of ovulation and the determination of the duration of the fertile period," Journal of Steroid Biochemistry, vol. 12, pp. 411-415, 1980.

D. B. Barr, L. C. Wilder, S. P. Caudill, A. J. Gonzalez, L. L. Needham, and J. L. Pirkle, "Urinary creatinine concentrations in the U. S. population: implications for urinary biologic monitoring measurements," Environmental Health Perspectives, vol. 113, pp. 192-200, 2005.

S. A. Barrett and J. B. Brown, "An evaluation of the method of Cox for the rapid analysis of pregnanediol in urine by gas-liquid chromatography," Journal of Endocrinology, vol. 47, pp. 471-480, 1970.

E. L. G. Beavis, J. B. Brown, and M. A. Smith, "Ovarian function after hysterectomy with conservations of the ovaries in pre-menopausal women," Journal of Obstetrics and Gynaecology of the British Commonwealth, vol. 76, pp. 969-978, 1969.

E. T. Bell, J. B. Brown, K. Fotherby, and J. A. Loraine, "Effect of a derivative of dithiocarbamoylhydrazine on hormone excretion during the menstrual cycle," Lancet, vol. 2, pp. 528-530, 1962.

J. A. Berges, "Ratios, regression statistics, and "spurious" correlations," Limnology and Oceanography, vol. 42, pp. 1006-1007, 1997.

D. Bernstein, H. B. Frishman, S. Levin, and S. Schwartz, "The value of urinary pregnanediol estimation for monitoring early pregnancies," Fertility and Sterility, vol. 29, pp. 141-143, 1978.

L. F. Blackwell, J. B. Brown, P. Vigil, B. Gross, S. Sufi, and C. d'Arcangues, "Hormonal monitoring of ovarian activity using the Ovarian Monitor, part I. Validation of home and laboratory results obtained during ovulatory cycles by comparison with radioimmunoassay," Steroids, vol. 68, pp. 465-476, 2003.

L. Blackwell, D. Cooke, and S. Brown, "Self-monitoring of fertility hormones: a new era for natural family planning?," Linacre Quarterly, vol. 85, pp. 26-34, 2018.

L. F. Blackwell, D. G. Cooke, and S. Brown, "The use of estrone-3-glucuronide and pregnanediol-3-glucuronide excretion rates to navigate the continuum of ovarian activity," Frontiers in Public Health, vol. 6, pp. 153, 2018.

L. F. Blackwell, P. Vigil, M. E. Alliende, S. Brown, M. Festin, and D. G. Cooke, "Monitoring of ovarian activity by measurement of urinary excretion rates using the Ovarian Monitor, part IV: the relationship of the pregnanediol glucuronide threshold, basal body temperature and cervical mucus as markers for the beginning of the post-ovulatory infertile period," Human Reproduction, vol. 31, pp. 445-453, 2016.

L. F. Blackwell, P. Vigil, D. G. Cooke, C. d'Arcangues, and J. B. Brown, "Monitoring of ovarian activity by daily measurement of urinary excretion rates of estrone glucuronide and pregnandediol glucuronide using the Ovarian Monitor, part III: Variability of normal menstrual cycle profiles," Human Reproduction, vol. 28, pp. 3306-3315, 2013.

L. F. Blackwell, P. Vigil, B. Gross, C. d'Arcangues, D. G. Cooke, and J. B. Brown, "Monitoring of ovarian activity by measurement of urinary excretion rates of estrone glucuronide and pregnanediol glucuronide using the ovarian monitor, part II: reliability of home testing," Human Reproduction, vol. 27, pp. 550-557, 2012.

R. Borth, B. Lunenfeld, and H. de Watteville, "Day-to-day variation in urinary gonadotrophin and steroid levels during the normal menstrual cycle," Fertility and Sterility, vol. 8, pp. 233-254, 1957.

J. B. Brown, "Types of ovarian activity in women and their significance: the continuum (a reinterpretation of early findings)," Human Reproduction Update, vol. 17, pp. 141-158, 2011.

J. B. Brown, P. Harrisson, and M. A. Smith, "Oestrogen and pregnanediol excretion through childhood, menarche and first ovulation," Journal of Biosocial Science, vol. 10, pp. 43-62, 1978.

J. B. Brown, R. Kellar, and G. D. Matthew, "Preliminary observations on urinary oestrogen excretion in certain gynaecological disorders," Journal of Obstetrics and Gynaecology of the British Empire, vol. 66, pp. 177-211, 1959.

S. Brown, "The distribution of phoneme inventory and language evolution," Cultural Anthropology and Ethnosemiotics, vol. 3, pp. 22-34, 2017.

S. Brown, L. F. Blackwell, and D. G. Cooke, "Online fertility monitoring: some of the issues," International Journal of Open Information Technologies, vol. 5, pp. 85-91, 2017.

S. Brown, D. G. Cooke, and L. F. Blackwell, "Monitoring the menstrual cycle using urine oestrone glucuronide: the relationship between excretion rate and concentration," International Journal of Basic Medical Sciences and Pharmacy, submitted, 2018.

M. G. Brush, R. W. Taylor, and R. Maxwell, "Gas chromatographic determination of urinary pregnanediol in toxaemia of pregnancy and suspected dysmaturity," Journal of Obstetrics and Gynaecology of the British Commonwealth, vol. 73, pp. 954-960, 1966.

R. D. Bulbrook, M. C. Swain, D. Y. Wang, J. L. Hayward, S. Kumaoka, O. Takatani, O. Abe, and J. Utsunomiya, "Breast cancer in Britain and Japan: plasma, oestradiol-17b, oestrone and progesterone, and their urinary metabolites in normal British and Japanese women," European Journal of Cancer, vol. 12, pp. 725-735, 1976.

D. G. Campbell, J. B. Brown, D. W. Fortune, R. Pepperell, and N. A. Beischer, "Excretion of oestrogens, pregnanediol and chorionic gonadotrophin in patients with hydatiform mole," Journal of Obstetrics and Gynaecology of the British Commonwealth, vol. 77, pp. 410-419, 1970.

C. B. Coulam, L. M. Hill, and R. Breckle, "Ultrasonic assessment of subsequent unexplained infertility after ovulation induction," British Journal of Obstetrics and Gynaecology, vol. 90, pp. 460-467, 1983.

M. G. Coyle, F. L. Mitchell, and C. S. Russell, "A report on the chromatographic assay of urinary pregnanediol in pregnancy," Journal of Obstetrics and Gynaecology of the British Empire, vol. 63, pp. 560-566, 1956.

J. M. Cruickshank, R. Morris, W. R. Butt, and C. S. Corker, "Inter-relationships between levels of plasma oestradiol, urinary total oestrogens and blood haemoglobin and neutrophil counts," Journal of Obstetrics and Gynaecology of the British Commonwealth, vol. 79, pp. 450-454, 1972.

O. A. Dada and B. Kwaku Adadevoh, "Total urinary oestrogen excretion during normal menstrual cycle and normal pregnancy in Nigerians," British Journal of Obstetrics and Gynaecology, vol. 82, pp. 40-43, 1975.

M. Desai, U. M. Donde, and M. I. Khatkhatay, "Feasibility of determination of fertile period in Indian women based on urinary hormone estimations," Indian Journal of Clinical Biochemistry, vol. 16, pp. 127-131, 2001.

W. P. Dmowski, R. Rao, and A. Scommegna, "The luteinized unruptured follicle syndrome and endometriosis," Fertility and Sterility, vol. 33, pp. 30-34, 1980.

E. J. Dudewicz and S. N. Mishra, Modern mathematical statistics. New York: John Wiley and Sons, Inc., 1988.

R. Ecochard and A. Gougeon, "Side of ovulation and cycle characteristics in normally fertile women," Human Reproduction, vol. 15, pp. 752-755, 2000.

R. Ecochard, R. Leiva, T. Bouchard, H. Boehringer, A. Direito, A. Mariani, and R. Fehring, "Use of urinary pregnanediol 3-glucuronide to confirm ovulation," Steroids, vol. 78, pp. 1035-1040, 2013.

B. R. Goldin, H. Adlercreutz, S. L. Gorbach, M. N. Woods, J. T. Dwyer, T. Conlon, E. Bohn, and S. N. Gershoff, "The relationship between estrogen levels and diets of Caucasian American and Oriental immigrant women," American Journal of Clinical Nutrition, vol. 44, pp. 945-953, 1986.

T. Höfer, H. Przyrembel, and S. Verleger, "New evidence for the theory of the stork," Paediatric and Perinatal Epidemiology, vol. 18, pp. 88-92, 2004.

M.-F. Jayle, "Excrétion des stéroïdes urinaires après administration de gonadotrophines chorioniques au cours du cycle menstruel," Comptes rendus des séances de la Société de biologie et de ses filiales, vol. 150, pp. 1351-1355, 1956.

S. Johnson, S. Weddell, S. Godbert, G. Freundl, J. Roos, and C. Gnoth, "Development of the first urinary reproductive hormone ranges referenced to independently determined ovulation day," Clinical Chemistry and Laboratory Medicine, vol. 53, pp. 1099-1108, 2015.

T. J. A. Key, D. Y. Wang, J. B. Brown, C. Hermon, D. S. Allen, J. W. Moore, R. D. Bulbrook, I. S. Fentiman, and M. C. Pike, "A prospective study of urinary oestrogen excretion and breast cancer risk," British Journal of Cancer, vol. 73, pp. 1615-1619, 1996.

R. A. Kronmal, "Spurious correlation and the fallacy of the ratio standard revisited," Journal of the Royal Statistical Society, vol. 156A, pp. 379-392, 1993.

R. Matthews, "Storks deliver babies (p = 0.008)," Teaching Statistics, vol. 22, pp. 36-38, 2000.

M. R. Neifeld, "A study of spurious correlation," Journal of the American Statistical Association, vol. 22, pp. 331-338, 1927.

J. Neyman, Lectures and conferences on mathematical statistics and probability, 2nd ed. Washington: Graduate School, U S Department of Agriculture, 1952.

A. D. Papanicolaou, D. A. Adamopoulos, J. A. Loraine, and S. F. Lunn, "Studies on the urinary excretion of gonadotrophins during the normal menstrual cycle in young women," Journal of Obstetrics and Gynaecology of the British Commonwealth, vol. 77, pp. 961-966, 1970.

A. D. Papanicolaou, J. A. Loraine, G. A. Dove, and N. B. Loudon, "Hormone excretion patterns in perimenopausal women," Journal of Obstetrics and Gynaecology of the British Commonwealth, vol. 76, pp. 308-316, 1969.

K. Pearson, "Mathematical contributions to the theory of evolution. On a form of spurious correlation which may arise when indices are used in the measurement of organs," Proceedings of the Royal Society of London, vol. 60, pp. 489-498, 1897.

R. D. Perrone, N. E. Madias, and A. S. Levey, "Serum creatinine as an index of renal function: new insights into old concepts," Clinical Chemistry, vol. 38, pp. 1933-1953, 1992.

T. Remer, A. Neubert, and C. Maser-Gluth, "Anthropometry-based reference values for 24-h urinary creatinine excretion during growth and their use in endocrine and nutritional research," American Journal of Clinical Nutrition, vol. 75, pp. 561-569, 2002.

J. Rock, G. Pincus, and C. R. Garcia, "Effects of certain 19-nor steriods on the normal human menstrual cycle," Science, vol. 124, pp. 891-893, 1956.

J. Roos, S. Johnson, S. Weddell, E. Godehardt, J. Schiffner, G. Freundl, and C. Gnoth, "Monitoring the menstrual cycle: comparison of urinary and serum reproductive hormones referenced to true ovulation," European Journal of Contraception and Reproductive Health Care, vol. 20, pp. 438-450, 2015.

W. Schlager, D. Marsal, P. A. G. van der Geest, and A. Sprenger, "Sedimentation rates, observation span, and the problem of spurious correlation," Mathematical Geology, vol. 30, pp. 547-556, 1998.

H. Sies, "A new parameter for sex education," Nature, vol. 332, pp. 495, 1988.

D. Stern, "Pregnanediol estimation: a rapid pregnancy test suitable for routine use," Journal of Obstetrics and Gynaecology of the British Empire, vol. 58, pp. 821-825, 1951.

J. M. Tanner, "Fallacy of per-weight and per-surface area standards and their relation to spurious correlation," Journal of Applied Physiology, vol. 2, pp. 1-15, 1949.

P. M. Wray and C. Scott Russell, "An investigation into the reliability of short specimens of urine for estimating daily pregnanediol excretion," Journal of Obstetrics and Gynaecology of the British Empire, vol. 64, pp. 526-530, 1957.


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