ISSN: 2455-5479
Archives of Community Medicine and Public Health
Case Report       Open Access      Peer-Reviewed

A Narrative Review of Natural History of Diseases and Continuity of Care in Family Medicine

Jose L Turabian

Family Doctor, Regional Health Service of Castilla La Mancha (SESCAM), Centro de Salud Benquerencia, Gadarrama s/n, Toledo, Spain
*Corresponding author: Jose L Turabian, Family Doctor, Regional Health Service of Castilla La Mancha (SESCAM), Centro de Salud Benquerencia, Gadarrama s/n, Toledo, Spain, E-mail: jturabianf@hotmail.com
Received: 15 May, 2017 | Accepted: 24 June, 2017 | Published: 26 June, 2017
Keywords: Continuity of Patient Care; Natural history of disease; Primary health care; Physician-Patient relations; Qualitative research; Family medicine

Cite this as

Turabian JL (2017) A Narrative Review of Natural History of Diseases and Continuity of Care in Family Medicine. Arch Community Med Public Health 3(1): 041-047. DOI: 10.17352/2455-5479.000023

Natural history of disease refers to the progression of a disease process in an individual over time. Family medicine has important epidemiological connotations, presenting a unique opportunity to study natural history of a disease. We present an example case of the natural history of the disease: the continued care of a patient with thromboangiitis obliterans for 37 years, who was continuously attended over many years in family medicine level, with the aim of reflecting and conceptualizing the importance that, for epidemiological knowledge of natural history of diseases have the data provide by family medicine, which can be classified as biopsychosocial typologies of the natural history of diseases, according to their pattern of natural history, and through an epidemiological classification directed by medical intervention. So, there are two complementary perspectives to characterize the natural history of the disease: that of the general practitioner, who through the medical records the entire process of each patient, and can determine both that there is a new health problem and its peculiarities; is an individualized vision. And the epidemiologist, who through the multiple health records he handles, and the support of biostatistics can discover a new disease and its evolution; is a population view. Future epidemiological strategies that use longitudinal study designs or “continuing care”, using homogeneous definitions of diseases, could play a pivotal role in better elucidating the controversies in natural history and the pathophysiology of subtypes of many common diseases, leading to improved clinical care. Cohort studies on the natural history of diseases should be enhanced in order to provide a basis for the development of health strategies and prevention and treatment measures. The ordinary general practitioners can make a significant contribution to research on the basis of patients seen in routine practice.

There was a time of adolescence when the green light dyed the walls dry and covered with plaster; then in the city it seemed that the cool vegetation froze the smoke of the houses in fog. Then it paled, lost all the colors ...: a dye of dry opal a little eclipsed by the centuries“.

Introduction

Natural history of disease refers to the progression of a disease process in an individual over time, in the absence of treatment. Although at present, the natural history of disease is affected by the medical or surgical treatment, and new drugs are going to change the natural history and epidemiology of many diseases worldwide. However, the global consequences will depend on treatment accessibility, and of medication adherence [1-5].

Natural history of disease represents the course of biological events between the sequential action of component causes (etiology) until the disease develops and the outcome occurs (healing, passing to chronicity or death). For example, untreated infection with HIV causes a spectrum of clinical problems beginning at the time of seroconversion (primary HIV) and terminating with AIDS and eventually death. In this example, it is now recognized that it may take 10 years or more for AIDS to develop after seroconversion [6]. Many, if not most, diseases have a characteristic natural history, although the time frame and specific manifestations of disease may vary from individual to individual and are influenced by preventive and therapeutic measures.

The interest of medicine to know the natural evolution of each disease is to discover the different stages and components of the pathological process, to can intervene as early as possible and change the course of the disease, in order to avoid the deterioration of health. There are two complementary perspectives to characterize the natural history of the disease: that of the general practitioner, who through the medical record records the entire process of each patient, and can determine both that there is a new health problem and its peculiarities; is an individualized vision. The epidemiologist, who through the multiple health records he handles, and the support of biostatistics can discover a new disease and its evolution; is a population view.

The person is the center of interest for the family doctor; but the importance of epidemiological research at the family physician level is often forgotten. This epidemiological level today is downplayed or underestimated; however, there have been family physician pioneers who studied the epidemiologic problems of their community with scientific rigor. Some of them have been recognized for their seminal work in the last 125 years [7-11].

In this context, we present an example-case of the natural history of the disease: the continued care of a patient with thromboangiitis obliterans for 37 years, including selected co-pathologies. The patient was continuously attended over many years in family medicine level, and it is presented with the aim of reflecting and conceptualizing the importance that, for epidemiological knowledge of natural history of diseases, have the data provide by family medicine.

Case Example

Thromboangiitis obliterans: a natural history for 37 years

1974: JRM was diagnosed of thromboangiitis obliterans, at 24 years of age, being a smoker of 20 cigarettes / day for 8 years. The onset symptomatology consisted of hypersensitivity to cold, with pain and coldness in both hands and feet. From its diagnosis, the disease followed a progressive course, with ulcerations in the right hand and both feet that forced the amputation of six fingers.

1981: In spite of the indication to suppress the tobacco, the patient did not stop smoking until 7 years after the diagnosis.

1986: The patient continued medical treatment with antiplatelet agents, peripheral circulation stimulants and calcium antagonists, and a sympathectomy was performed.

1995: The patient quit smoking.

2001: Six years after quitting smoking, the patient began to experience improvement in his symptoms but still needed medical attention and cures for his skin lesions.

2004: Certain hematological alterations (hemoglobin increase and thrombocytosis) that are related to thromboangiitis obliterans are maintained.

2007: After 12 years of quitting smoking, the symptoms had practically disappeared and there was no recurrence of ulcerations, reducing the requirement for analgesics.

2008: It is diagnosed of type 2 diabetes mellitus.

2009: From 1986 to this date has maintained the treatment of nifedipine and analgesics.

2010: Ureteral carcinoma (bladder tumor) grade II-III is diagnosed and transurethral resection and percutaneous nephrectomy are performed, as well as chemotherapeutic treatment. There is a left common femoral vein thrombosis.

2011: The patient presents venous thrombosis in lower right limb. There is sepsis of urinary origin. Pulmonary, bony, thoracic, hepatic, and splenic metastases are found. The patient dies at 60 years of age.

Discussion

The relationship between continuity of care in family medicine and the epidemiological knowledge of the natural history of diseases

Family medicine is a major source of information about health problems and their evolution. For most illnesses the general practitioner is the first point of contact in the health care system and he looks after a population whose age and sex composition is known. He is therefore in an ideal position to conduct inquiries about natural history of disease (the factors predisposing, precipitating and perpetuating the disease). The essence of family medicine is to assist individuals in families and communities, and this implies, on the one hand a good continuity of care, and moreover a knowledge of the nature of diseases in the community.

The continuity of care is considered as a defining characteristic of family medicine and primary health care [12-18], although it can be seen from different perspectives, suggesting a hierarchy of dimensions from less to more complexity (Table 1) [19-23].

In medicine a priority objective of the studies must be the knowledge of the natural history of the disease [24]. Family medicine presents a unique opportunity to study the natural history of disease and allows the establishment of patient-physician-family-community relationships. Family doctor work includes the natural history of disease and the human life cycle, and so, no one is better able to observe, from family history, the ultimate consequences of any health problem (Figure 1) [25-28]. The simplest and most basic way to achieve effective care is by continuing care [25].

A case example of thromboangiitis obliterans

Although our main interest in this article is not to communicate a clinical case, but to present it as an example of the ideal position of the family physician to observe the natural history of the diseases, thanks to his work of continuous care [25], this clinical observation agrees With other publications where patients were followed for several years, and those who stopped smoking responded better to treatment and evolved more favorably than those who did not [29,30]. Our patient needed 6 years of smoking cessation to begin to notice improvement in his symptoms, and throughout the 17 years that passed without smoking evolved towards the disappearance of ulcerations and improvement of pain. Finally, another disease possibly related also to tobacco and in the context of its vascular problem, causes the fatal outcome.

The natural history of diseases

The process begins with the appropriate exposure to or accumulation of factors sufficient for the disease to begin in a susceptible host. For an infectious disease, the exposure is a microorganism. For cancer, the exposure may be a factor that initiates the process, such as asbestos fibers or components in tobacco smoke (for lung cancer), or one that promotes the process, such as estrogen (for endometrial cancer).

After the disease process has been triggered, pathological changes then occur without the individual being aware of them. This stage of subclinical disease, extending from the time of exposure to onset of disease symptoms, is usually called the incubation period for infectious diseases, and the latency period for chronic diseases. During this stage, disease is said to be asymptomatic (no symptoms) or unapparent. This period may be as brief as seconds for hypersensitivity and toxic reactions to as long as decades for certain chronic diseases. Even for a single disease, the characteristic incubation period has a range. For example, the typical incubation period for hepatitis A is as long as 7 weeks. The latency period for leukemia to become evident among survivors of the atomic bomb blast in Hiroshima ranged from 2 to 12 years, peaking at 6–7 years [31].

Although disease is not apparent during the incubation period, some pathologic changes may be detectable with laboratory, radiographic, or other screening methods. Most screening programs attempt to identify the disease process during this phase of its natural history, since intervention at this early stage is likely to be more effective than treatment given after the disease has progressed and become symptomatic.

The onset of symptoms marks the transition from subclinical to clinical disease. Most diagnoses are made during the stage of clinical disease. In some people, however, the disease process may never progress to clinically apparent illness. In others, the disease process may result in illness that ranges from mild to severe or fatal. This range is called the spectrum of disease. Ultimately, the disease process ends either in recovery, disability or death.

Because the spectrum of disease can include asymptomatic and mild cases, the cases of illness diagnosed by clinicians in the community often represent only the tip of the iceberg. Many additional cases may be too early to diagnose or may never progress to the clinical stage. Unfortunately, persons with unapparent or undiagnosed infections may nonetheless be able to transmit infection to others. The challenge to public health workers is that these carriers, unaware that they are infected and infectious to others, are sometimes more likely to unwittingly spread infection than are people with obvious illness [32].

Man is subject to a great variety of diseases and it has always been one of the main functions of clinical research to provide accurate descriptions of these various pathologic entities. The characteristics of most acute diseases and of the acute phases of most chronic diseases have been reasonably well defined. With some notable exceptions, however, accurate descriptions of the entire courses of common, chronic conditions are woefully lacking.

Some ways of classifying and systematizing the study of the natural history of diseases

A- Biopsychosocial typologies (classification biopsychosocial of etiologies) of the natural history of diseases:

A typology of the natural history of diseases can be established [33]:

∗ Beginning: acute / gradual

∗ Course: progressive, constant, recurrent

∗ Result: non-fatal, limiting life expectancy, fatal.

∗ Inability: no disability, moderate, severe

∗ Grade of uncertainty or predictability.

∗ Other factors: Visibility of symptoms; Severity of crises; Genetic contribution; Treatment regime

With these variables a relationship matrix (Table 2) can be constructed. However, there are some diseases that can be located in different places, and these cannot be placed with some certainty in that matrix.

B-A classification of diseases according to their pattern of natural history

Different diseases affect people at different ages and their course and results differ. Five patterns of the natural history of diseases can be described [34-60]:

1. The common disease pattern in children. For example: catarrhal syndrome, umbilical hernia, nevus “strawberry”, growing pains, enuresis, etc. They have high incidence and prevalence during a plateau and a descent to a level of low incidence that is maintained.

2. Many diseases become more prevalent with age and some become serious. For example: osteoarthritis, coronary heart disease, stroke, peripheral arteriopathy, hypertension, COPD and cancers. There is a plateau of low incidence and prevalence, followed by an increase from the average age of life to a plateau of high prevalence and incidence.

3. Some diseases are “once and always”. That is, once they arise they persist all their lives. Example: some congenital diseases such as Down syndrome and cystic fibrosis, and acquired diseases such as diabetes, hypothyroidism, blindness and deafness. They present a constant plateau of prevalence and incidence.

4. Some diseases appear to follow a course and disappear: they tend to appear early in the middle of adulthood. There is a period of clinical activity, persistent or intermittent, that can last 10-20 years and then the symptoms decrease or disappear. Examples: asthma, migraine, allergic rhinitis, low back pain, duodenal ulcer, anxiety, depression, urinary tract infections in women, and various gynecological problems.

5. Some diseases with high prevalence and incidence in young and old. They include bronchial hyperreactivity, hydrocele, hernias and constipation.

An epidemiological classification directed by medical intervention

The diseases can be grouped into three blocks, following an epidemiological classification directed by medical intervention [61]:

a) Diseases whose etiology is understood sufficiently for prevention (for example: coronary heart disease, adverse drug reactions, pulmonary tuberculosis, stroke, traffic accidents).

b) Diseases whose etiology is only partially known but for which there are proposed screening or prevention approaches (for ezample, breast cancer, bladder cancer, prostatic hypertrophy, hypertension and genetic diseases).

c) Diseases whose etiology is not well known and where it is not possible to implement prevention or screening (for example, senile dementia, hyperparathyroidism, ovarian cancer, Paget’s disease and lymphoma).

Conclusion

Family medicine has important epidemiological connotations, presenting a unique opportunity to study natural history of a disease. So, there are specific implications for epidemiology in family medicine which have not been sufficiently systematized conceptually [62,63]. There have been family physician pioneers who studied the epidemiologic problems of their community with scientific rigor. Some of them have been recognized for their seminal work in the last 125 years [7-10,64-68]. Because of their detailed reports, they were able to discover what was contained in their practice, improve their clinical tasks and improving the knowledge of the natural history of the diseases. These pioneers made much of this original work based on their observations of individuals for years; it is what we call “continuing care” [21]. For example, James Mackenzie [7,25] performed much of his original work based on observation of individuals for years. The accumulation of knowledge about the disease can be obtained in family medicine, but requires an effort of observation and good records.

Further studies are needed to better elucidate and overcome the present limitations represented by the lack of large prospective longitudinal investigations. Future epidemiological strategies that use longitudinal study designs or “continuing care”, using homogeneous definitions of diseases, could play a pivotal role in better elucidating the controversies in natural history and the pathophysiology of subtypes of many common diseases, leading to improved clinical care. Cohort studies on the natural history of diseases should be enhanced in order to provide a basis for the development of health strategies and prevention and treatment measures.

As drug development and technology continues to improve, it will be important to design rationale longitudinal clinical studies enrolling patient populations that represent the overall population, including racial minorities, gender differences, the elderly, and with the presence of co-morbidities, so that studies results can be appropriately extrapolated. Future research should focus on elaborating the causal framework that leads to the development and persistence of severe common diseases, with an emphasis on identifying modifiable factors for intervention by policy makers or health professionals. Further, more research is needed on the natural history of diseases in low-income and middle-income countries, from the patient’s perspective, and relating the natural history of diseases with the family life cycle and family transitions [69-71].

The ordinary general practitioners can make a significant contribution to research on the basis of patients seen in routine practice. It does not need the usual obsession for statistics, but an equivalent clinical mentality to that of Alexander Fleming -to realize the patchy shape in Petri disk which turns up in surgery: yeast floats through the windows, lands on a plate of germs, and kills them; it is penicillin. The trick is to know what to notice, and what to ignore [72].

  1. Keshava HB, Rosen JE, DeLuzio MR, Kim AW, Detterbeck FC, et al. (2017) "What if I do nothing?" The natural history of operable cancer of the alimentary tract. Eur J Surg Oncol 43: 788-795. Link: https://goo.gl/4N9n9a
  2. Rosen JE, Keshava HB, Yao X, Kim AW, Detterbeck FC, et al. (2016) The Natural History of Operable Non-Small Cell Lung Cancer in the National Cancer Database. Ann Thorac Surg 101: 1850-1855. Link: https://goo.gl/S6ztBc
  3. Kazandjian D (2016) Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol 43: 676-681. Link: https://goo.gl/xxRsZD
  4. Ponziani FR, Mangiola F, Binda C, Zocco MA, Siciliano M, Grieco A, et al. (2017) Future of liver disease in the era of direct acting antivirals for the treatment of hepatitis C. World J Hepatol 9: 352-367. Link: https://goo.gl/VzfGCA
  5. Du L, Cheng Z, Zhang Y, Li Y, Mei D (2017) The impact of medication adherence on clinical outcomes of coronary artery disease: A meta-analysis. European Journal of Preventive Cardiology 24: 962-970. Link: https://goo.gl/Tnf7z9
  6. Mindel A, Tenant-Flowers M (2001) ABC of AIDS: Natural history and management of early HIV infection. BMJ 332: 1290–1293. Link: https://goo.gl/oVoEMM
  7. Mackenzie J (2012) A Defence of the Thesis that “The opportunities of the general practitioner are essential for the investigation of disease and the progress of medicine”. Int J Epidemiol 41: 1507-1518. Link: https://goo.gl/Bw8ebe
  8. Smith BH, Guthrie B, Sullivan FM, Morris AD (2012) Commentary: A thesis that still warrants defence and promotion. Int J Epidemiol 41: 1518-1522. Link: https://goo.gl/hEXJu2
  9. Baker R (2012) Commentary: James Mackenzie 1921, still relevant in 2012. Int J Epidemiol 41: 1523-1525. Link: https://goo.gl/5mzcLC
  10. Hart JT (2013) Commentary: Sir James Mackenzie (1853–1925): An ambiguous pioneer for research in primary care. Int J Epidemiol 41: 1525-1531. Link: https://goo.gl/qS9jDU
  11. Turabian JL, Báez-Montiel B, Gutiérrez-Islas E (2016) Implications of Incidence Rates of Diseases at Local Level in Family Medicine. Scientific Pages Fam Med 1: 02. Link: https://goo.gl/KzX8HP
  12. Fry J (1992) Common Diseases: Their Nature Incidence and Care. Lancaster, England: MTP Press Limited. Link: https://goo.gl/svesha
  13. White ES, Gray DP, Langley P, Evans PH (2016) Fifty years of longitudinal continuity in general practice: a retrospective observational study. Fam Pract 33: 148-153. Link: https://goo.gl/65vX4V
  14. Gérvas J, Ortún V (1995) Caracterización del trabajo asistencial del medico General/de familia. Aten Primaria 16: 501-506. Link: https://goo.gl/bDJUfW
  15. 15.-Beaulieu M-D (2013) Teaching the essence of family medicine. Can Fam Physician. Sep; 59: 1017. Link: https://goo.gl/BrDJxG
  16. Stokes T, Tarrant C, Mainous III AG, Schers H, Freeman G, et al. (2005) Continuity of Care: Is the Personal Doctor Still Important? A Survey of General Practitioners and Family Physicians in England and Wales, the United States, and the Netherlands. Ann Fam Med 3: 353-359. Link: https://goo.gl/qUqC23
  17. Hill AP, Freeman GK (2011) Continuity of care. Promoting Continuity of Care in General Practice. RCGP Policy Paper. The Royal College of General Practitioners. Link: https://goo.gl/SEj5ju
  18. Sayer S, Lee TH (2014) Time after Time — Health Policy Implications of a Three-Generation Case Study. N Engl J Med 371:1273-1276. Link: https://goo.gl/tePQGb
  19. Saultz JW (2003) Defining and Measuring Interpersonal Continuity of Care. Ann Fam Med 1: 134-143. Link: https://goo.gl/P1gR6i
  20. Alazri MH, Neal RD, Heywood P, Leese B (2006) Patients' experiences of continuity in the care of type 2 diabetes: a focus group study in primary care. Br J Gen Pract 56: 488-495. Link: https://goo.gl/gbT6ER
  21. Richards H (2009) We must defend personal continuity in primary care. BMJ 339:b3923. Link: https://goo.gl/SYPM3M
  22. Schers H, van den Hoogen H, Grol R, van den Bosch W (2006) Continuity of care through medical records-an explorative study on GPs' management considerations. Fam Pract 23: 349-352. Link: https://goo.gl/q3ZZwW
  23. Naithani S, Gulliford M, Morgan M (2006) Patients' perceptions and experiences of 'continuity of care' in diabetes. Health Expect; 9: 118-129.  Link: https://goo.gl/eNUzEp
  24. Martinez López de Letona J (2008) La historia natural de la enfermedad como fuente esencial para la formulación del pronóstico. Monografías del Grupo Hospital de Madrid. Madrid: Editorial Materia. Link: https://goo.gl/USdx5Y
  25. Morrell D (1991) The art of general practice. Oxford: Oxford University Press.
  26. Bigelow J. (1854) A discourse on self-limited diseases, delivered before the Massachusetts Medical Society at their annual meeting, May 27, 1835. Boston: Nathan Hale. [digital copy of a book]. Link: https://goo.gl/ssR2LA
  27. Freeman GK, Olesen F, Hjortdahl P (2003) Continuity of care: an essential element of modern general practice? Fam Pract; 20: 623-627. Link: https://goo.gl/KjMrNp
  28. Woo B (2006) Primary Care — The Best Job in Medicine? N Engl J Med; 355: 864-866. Link: https://goo.gl/5B4CWm
  29. Fernández-Miranda C, Rubio R, Vicario JL, Arnaiz A, Férnandez Sáez R, Mollejo M, et al. (1993) Tromboangeitis obliterante (enfermedad de Buerger). Estudio de 41 casos. Med Clin (Barc); 101: 321-326. Link: https://goo.gl/6Sfae2
  30. Szuba A, Cooke JP (1998) Thromboangiitis obliterans. An update on Buerger's disease. West J Med Apr; 168: 255–260. Link: https://goo.gl/EoYm8y
  31. Philippe P (1994) Sartwell's incubation period model revisited in the light of dynamic modelling. Journal of Clinical Epidemiology; 47: 419-433. Link: https://goo.gl/XfsNMe
  32. Centers for Disease Control and Prevention (2012) Principles of Epidemiology in Public Health Practice, Third Edition. An Introduction to Applied Epidemiology and Biostatistics Lesson 1: Introduction to Epidemiology. Section 9: Natural History and Spectrum of Disease. Link: https://goo.gl/BN8K5u
  33. Rolland JS (1994) Families, illness, and disability. An integrative treatment model. New York: Bassic Books.
  34. Fry J (1992) Common Diseases: Their Nature Incidence and Care. Lancaster, England: MTP Press Limited. Link: https://goo.gl/Qcz6Rh
  35. Murray SA, Kendall M, Boyd K, Sheikh A (2005) Illness trajectories and palliative care. BMJ; 330:1007. Link: https://goo.gl/vt6KYj
  36. Kuchibhatla MN, Fillenbaum GG, Hybels CF, Blazer DG (2012) Trajectory classes of depressive symptoms in a community sample of older adults. Acta Psychiatr Scand 125: 492-501. Link: https://goo.gl/DoJ71Q
  37. Goodin DS (2016) The epidemiology of multiple sclerosis: insights to a causal cascade. Handb Clin Neurol 138: 173-206. Link: https://goo.gl/iCA8Rr
  38. Chaudhry SP, Stewart GC (2016) Advanced Heart Failure: Prevalence, Natural History, and Prognosis. Heart Fail Clin Jul 12: 323-33. Link: https://goo.gl/rCJ6kM
  39. Amstutz HC, Le Duff MJ (2016) The Natural History of Osteoarthritis: What Happens to the Other Hip? Clin Orthop Relat Res 474: 1802-1809. Link: https://goo.gl/nzSkqM
  40. Sarvet AL, Hasin D (2016) The natural history of substance use disorders. Curr Opin Psychiatry 29: 250-257. Link: https://goo.gl/HHmge9
  41. Savarino E, Marabotto E, Bodini G, Pellegatta G, Coppo C, et al. (2017) Epidemiology and natural history of gastro-esophageal reflux disease. Minerva Gastroenterol Dietol [Epub ahead of print]. Link: https://goo.gl/PkTW52
  42. Yang W, Huang J (2017) Chronic Subdural Hematoma: Epidemiology and Natural History. Neurosurg Clin N Am 28: 205-210. Link: https://goo.gl/ojUyRM
  43. Lynch KL, Yang YX, Metz DC, Falk GW (2017) Clinical presentation an disease course of patients with esophagogastric junction outflow obstruction. Dis Esophagus 30: 1-6. Link: https://goo.gl/KCWkqF
  44. Mahr A, Aouba A, Richebé P, Gonzalez-Chiappe S (2017) [Epidemiology and natural history of giant cell arteritis]. [Article in French]. [Epub ahead of print]. Rev Med Interne Link: https://goo.gl/H511Tc
  45. Tsodikov A, Gulati R, de Carvalho TM, Heijnsdijk EAM, Hunter-Merrill RA, et al. (2017) Is prostate cancer different in black men? Answers from 3 natural history models. Cancer [Epub ahead of print]. Link: https://goo.gl/DGFbHt
  46. Ingles J, Burns C, Bagnall RD, Lam L, Yeates L, Sarina T, et al. (2017) Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. Circ Cardiovasc Genet  Link: https://goo.gl/7LMS7T
  47. Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, et al. (2016) Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA. Alzheimers Dement 12: 292-323. Link: https://goo.gl/Qk2fRH
  48. Price MJ, Ades AE, Soldan K, Welton NJ, Macleod J, et al. (2016) The natural history of Chlamydia trachomatis infection in women: a multi-parameter evidence synthesis. Health Technol Assess 20: 1-250 Link: https://goo.gl/Qa2WMg
  49. Gainza Miranda D, Sanz Peces EM, Alonso Babarro A, Prados Sánchez MC, Varela Cerdeira M (2016 ) HOLD study (Home care Obstructive Lung Disease): natural history of patients with advanced COPD. BMC Palliat Care 15:35. Link: https://goo.gl/eFVcHt
  50. Chen W, Marra CA, Lynd LD, FitzGerald JM, Zafari Z, Sadatsafavi M (2016) The natural history of severe asthma and influences of early risk factors: a population-based cohort study. Thorax 71: 267-75. Link: https://goo.gl/VQGbkt
  51. Lienert JP, Tarko L, Uchino M, Christen WG, Schaumberg DA (2016) Long-term Natural History of Dry Eye Disease from the Patient's Perspective. Ophthalmology 123: 425-433. Link: https://goo.gl/TYPauJ
  52. Lingala S, Ghany MG (2015) Natural History of Hepatitis C. Gastroenterol Clin North Am; 44: 717-734. Link: https://goo.gl/e683Kt
  53. Sgalla G, Biffi A, Richeldi L (2016) Idiopathic pulmonary fibrosis: Diagnosis, epidemiology and natural history. Respirology 21: 427-437. Link: https://goo.gl/LjN8cL
  54. Silverstein MD, Reed CE, O'Connell EJ, Melton LJ, O'Fallon WM, et al. (1994) Long-Term Survival of a Cohort of Community Residents with Asthma. N Engl J Med 331:1537-1541. Link: https://goo.gl/Npr1KL
  55. Nevillen RG, McCowan C, Hoskins G, Thomas G (2001) Cross-sectional observations on the natural history of asthma. Br J Gen Pract May 51: 361–365. Link: https://goo.gl/gWXM4F
  56. Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D (2001) Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 358: 1682-1686. Link: https://goo.gl/MqGrHU
  57. McWhinney IR (1989) A textbook of Family Medicine. New York: Oxford University Press. Link: https://goo.gl/oZLwzX
  58. Capell HA, Murphy EA, Hunter JA (1991) Rheumatoid arthritis: workload and outcome over 10 years. Q J Med 79: 461-476. Link: https://goo.gl/86U86E
  59. Sagie A, Larson MG, Levy D (1993) The Natural History of Borderline Isolated Systolic Hypertension. N Engl J Med 329: 1912-1917. Link: https://goo.gl/u5aX9A
  60. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, et al. (1995) Natural History of Peripheral Neuropathy in Patients with Non-Insulin-Dependent Diabetes Mellitus, N Engl J Med 333: 89-94. Link: https://goo.gl/rf5c22
  61. Peach H, Heller RF (1984) Epidemiology of commom diseases. London: William Heinemann Medical Books Limited. Link: https://goo.gl/cyKNG8
  62. Turabián JL, Moreno-Ruiz S, Cucho-Jove R (2016) “Doctor, I have Chikungunya”. Conceptual systematisation of specific epidemiological implications in family medicine. Semergen 42: 488-491. Link: https://goo.gl/qozV45
  63. Turabian JL, Moreno-Ruiz S, Cucho-Jove R (2016) Epidemiology in Family Medicine. J Gen Pract (Los Angel) 4: 278. Link: https://goo.gl/cxc8xH
  64. Green LA, Hickner J (2006) A Short History of Primary Care Practice-based Research Networks: From Concept to Essential Research Laboratories. J Am Board Fam Med 19: 1-10. Link: https://goo.gl/E2RFjW
  65. Hart JT (1970) Semicontinuous screening of a whole community for hypertension. Lancet 2: 223-226. Link: https://goo.gl/gQZ2vU
  66. Hart JT (1974) Milroy Lecture: the marriage of primary care and epidemiology: continuous anticipatory care of whole populations in a state medical service. J R Coll Physicians Lond 8: 299-314. Link: https://goo.gl/U7HyAB
  67. Hart JT (1975) Management of high blood pressure in general practice. Butterworth Gold Medal essay. J R Coll Gen Pract 25: 160-192. Link: https://goo.gl/o4nRiU
  68. Hart JT, Thomas C, Gibbons B, Edwards C, Hart M, et al. (1991) Twenty five years of case finding and audit in a socially deprived community. BMJ 302: 1509. Link: https://goo.gl/ftTjpX
  69. Johnson N, Lancaster T, Fuller A, Hodgson SV (1995) The prevalence of a family history of cancer in general practice. Fam Pract 12: 287-289. Link: https://goo.gl/LD2ec1
  70. Turabián JL, Báez-Montiel B and Gutiérrez-Islas E (2016) Type of Presentation of Coronary Artery Disease According the Family Life Cycle. SM J Community Med 2: 1019. Link: https://goo.gl/3osVzy
  71. Turabián JL, Franco BP (2016) Turning Points and Transitions in the Health of the Patients: A Perspective from Family Medicine. J Family Med Community Health 3: 1087. Link: https://goo.gl/vJwdWB
  72. Charlton B (1997) Serendipity. Br J Gen Pract 47: 868. Link: https://goo.gl/mK3eYL
© 2017 Turabian JL. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.