NATIONAL DEATH INDEX A computerized central registry of deaths in the United States, started in 1979 and operated by the U.S. National Center for Health Statistics, which facilitates mortality follow-up. See also canadian mortality database.

NATURAL EXPERIMENT Naturally occurring circumstances in which subsets of the population have different levels of exposure to a supposed causal factor in a situation resembling an actual experiment, where human subjects would be randomly allocated to groups. The presence of persons in a particular group is typically nonrandom; yet for a natural experiment, it suffices that their presence is independent of (unrelated to) potential confounders. See also experiment; experimental epidemiology; observa- tional study.

Investigation by John Snow (1813–1858) of the distribution of cholera cases in London in relation to the sources of water supply is an excellent example of a natural experiment. It would have been unethical for Snow to allocate subjects to groups exposed to a lethal infection; but tracing the source of their drinking water, using what is now sometimes called shoe-leather epidemiology, gave him the opportunity to make crucially important observations. “To turn this grand experiment to account, all that was required was to learn the supply of water to each individual house where a fatal attack of cholera might occur …. I resolved to spare no exertion which might be necessary to ascertain the exact effect of the water supply on the progress of the epidemic, in the places where all the circumstances were so happily adapted for the inquiry…. I had no reason to doubt the correctness of the conclusions I had drawn from the great number of facts already in my possession, but I felt that the circumstances of the cholera-poisoning passing down the sewers into a great river, and being distributed through miles of pipes, and yet producing its specific effects was a fact of so startling a nature, and of so vast importance to the community, that it could not be too rigidly examined or established on too firm a basis.”289

NATURAL FOCUS OF INFECTION (Syn: natural nidality of disease). A focus existing outside a human population (e.g., in domestic or wild animals) often transmitted by a vector; humans can be infected if they enter such a biotype. The concept was developed and studied by the Soviet-era Russian epidemiologist A. D. Pavlovsky.

NATURAL HISTORY OF DISEASE The course of a disease from pathological onset or inception to resolution. Many diseases have certain relatively well-defined stages that taken all together, are referred to as the “natural history of the disease” in question. These stages are as follows:

  1. Stages of pathological onset. They are constantly being changed in many diseases;
    “onset,” in particular, tends to be redefined in increasingly smaller microbiological
    (e.g., molecular and genetic) terms.
  1. Presymptomatic stage: from initiation of disease to the first appearance of symptoms
    and/or signs.
  1. Clinically manifest disease, which may progress inexorably to a fatal termination, be
    subject to remissions and relapses, or regress spontaneously, leading to recovery.

The nature and borders of these broad stages varies vastly across diseases. Some diseases have precursors. For example, elevated serum cholesterol is among the precursors of coronary heart disease. Precursor lesions may long precede the stage of pathological onset, but many alterations will be reversible or of unknown prognostic significance. An intense search is presently taking place for genetic, biochemical, or peptidomic “precursors” or “markers” of many diseases; a common aim is to market tests for early detection, which should be able to alter the natural history of the disease if they are promptly followed by effective interventions (e.g., surgical treatment). Studies on precursor and prognostic factors must integrate evidence on the putative biochemical or molecular markers with clinical, anatomopathological, and pathophysiological reasoning. Often it is more a model or framework than a reality: the presentation and course of human disease tends to vary a lot in different individuals and contexts. The term natural should not be taken as a synonym of biological, since the course of disease in humans is not influenced only by biological and health care processes but also by social and cultural interactions (e.g., by cultural beliefs and norms on health care seeking, attributions of meaning to symptoms, economic barriers to treatment).124 The term has also been used to mean “descriptive epidemiology of disease.” See also sickness “career”; early clinical detection; clinical

study; incubation period; induction period; latency period; screening.
NATURAL HISTORY STUDY A study, generally longitudinal, designed to yield informa-

tion about the natural course of a disease or condition. See also inception cohort. NATURAL RATE OF INCREASE (DECREASE) See growth rate of population. NCHS National Center for Health Statistics (United States) (
NEAREST NEIGHBOR METHOD A means of analyzing the spatial patterns of a free-

living population. A term from veterinary epidemiology. Random sampling points are located throughout an area and the distance from each point to the nearest individual is measured; alternatively, individuals are selected at random and, from each of these, the distance to the nearest neighbor is measured.

NECESSARY CAUSE A causal factor whose presence is required for the occurrence of the effect. See also association; causality; causation of disease, factors in; compo- nent causes; diseases of complex etiology; Evans’s postulates; Hill’s criteria of causation; integration; sufficient cause.

NEEDLE STICK Puncture of the skin by a needle that may have been contaminated by contact with an infected patient or fluid. See also sharps.

NEED(S) In health economics, the minimum amount of resources required to exhaust an individual’s or a specified population’s capacity to benefit from an intervention.1 In other contexts, need is variously and often vaguely defined. Sociologists allude to perceived need, meaning the beliefs or perceptions of health care providers or users about their requirements. Physicians speak of professionally defined needs, meaning undiagnosed

165 Net reproduction rate (NRR)

and/or untreated conditions ranging from dangers to the public health, such as the risk of TB posed by persons who are excreting tubercle bacilli in sputum, to mild myopia or astigmatism in persons who would benefit from wearing corrective lenses.

NEEDS ASSESSMENT A systematic procedure for determining the nature and extent of problems experienced by a specified population that affect their health either directly or indirectly. Needs assessment makes use of epidemiological, sociodemographic, and qualitative methods to describe health problems and their environmental, social, eco- nomic, and behavioral determinants. The aim is to identify unmet health care needs and make recommendations about ways to address these needs, whether they are explicit health problems such as untreated diseases or “problems waiting to happen,” such as inadequate housing, ignorance due to low literacy levels, domestic violence, lack of access to long-term care, etc. Needs assessment is either a routine or an ad hoc activity in many local public health departments.290

NEGATIVE PREDICTIVE VALUE See predictive value, negative.
NEGATIVE STUDY Often taken to mean a study that fails to find evidence for an effect. It is a somewhat confusing term because it also suggests a “negative effect,” which in turn may mean a preventive or a deleterious effect. See also confounding, negative;

false negative; null study.


  1. In vital statistics, the number of deaths in infants under 28 days of age in a given period, usually a year, per 1000 live births in that period.
  1. In obstetrical and perinatal research, the term neonatal mortality rate is often used to denote the cumulative mortality rate of live-born infants within 28 days of age. See death rate.

NESTED CASE-CONTROL STUDY An important type of case-control study in which cases and controls are drawn from the population in a fully enumerated cohort. Typi- cally, some data on some variables are already available about both cases and controls; thus concerns about differential (biased) misclassification of these variables can be reduced (e.g., environmental or nutritional exposures may be analyzed in blood from cases and controls collected and stored years before disease onset). A set of controls is selected from subjects (i.e., noncases) at risk of developing the outcome of interest at the time of occurrence of each case that arises in the cohort.12,31,97,291

NESTED DESIGN A study design that is applied to a population already identified in an existing population or study; an example is a nested case-control study, in which cases and controls are drawn from a fully enumerated cohort, which may already be under investigation in a cohort study.

NET MIGRATION The numerical difference between immigration and emigration.
NET MIGRATION RATE The net effect of immigration and emigration on an area’s population, expressed as an increase or decrease per 1000 population of the area in a

given year.
NET REPRODUCTION RATE (NRR) The average number of female children born per

woman in a cohort subject to a given set of age-specific fertility rates, a given set of age- specific mortality rates, and a given sex ratio at birth. This rate measures replacement fertility under given conditions of fertility and mortality: it is the ratio of daughters to mothers assuming continuation of the specified conditions of fertility and mortality. It is a measure of population growth from one generation to another under constant condi- tions. This rate is similar to the gross reproduction rate but takes into account that some

Net reproductive rate (r) 166

women will die before completing their childbearing years. An NRR of 1.00 means that each generation of mothers is having exactly enough daughters to replace itself in the population. See also gross reproduction rate; replacement-level fertility.

NET REPRODUCTIVE RATE (R) (Syn: case reproduction rate) In infectious disease epi- demiology, the average number of secondary cases that will occur in a mixed host popu- lation of susceptibles and nonsusceptibles when one infected individual is introduced. Its relationship to the basic reproductive rate (R0) is given by

R = R0 x

where x is the proportion of the host population that is susceptible. NEUROEPIDEMIOLOGY A branch or subspecialty of epidemiology that studies factors influencing the occurrence of disorders and diseases affecting the nervous system, like Parkinson’s disease and multiple sclerosis. Primary outcomes include incidence, preva- lence, survival, and mortality from neurological diseases. As mentioned above, this dic-

tionary includes definitions for just a few branches of epidemiology.
NGO Nongovernmental organization.
NHANES National Health and Nutrition Examination Survey (of the National Center for

Health Statistics).
NHMRC National Health and Medical Research Council (Australia) ( NIDUS A focus of infection. The term can be used to describe any heterogeneity in the

distribution of a disease, but it is usually applied to a small area in which conditions favor occurrence and spread of a communicable disease. Also, the site of origin of a pathological process.

NIH National Institutes of Health (United States) (
NIOSH National Institute for Ocupational Safety and Health (United States) (www.niosh.

NNT See Number Needed to Treat.
NNH See Number Needed to Harm.
NNS See Number Needed to Screen.
NOCEBO An unpleasant or adverse effect attributable to administration of a placebo. N-OF-ONE STUDY (Syn: single-patient trial) A variation of a randomized controlled

crossover clinical trial, in which a sequence of alternative treatments is randomly allocated to only one patient. Changes in signs and symptoms (or other reversible out- comes) experienced by the patient are compared, with the aim of deciding on the opti- mal regimen for the patient.292–294

NOISE (IN DATA) This term is used when extraneous uncontrolled variables and/or errors influence the distribution of measurements made in a study, thus rendering diffi- cult or impossible the determination of relationships between variables under scrutiny.

NOMENCLATURE A list of all approved terms for describing and recording observations. NOMINAL SCALE See measurement scale.
NOMOGRAM A form of line chart showing scales for the variables involved in a particu-

lar formula in such a way that corresponding values for each variable lie on a straight

line intersecting all the scales.
NONCONCURRENT STUDY See historical cohort study. NONDIFFERENTIAL MISCLASSIFICATION See misclassification.

NONEXPERIMENTAL STUDY See observational study.

NONGENOTOXIC CARCINOGENS Carcinogens that do not cause direct damage to the DNA. Nongenotoxic processes and mechanisms include induction of inflamma- tion, immunosuppression, formation of reactive oxygen species (ROS), activation of receptors such as the arylhydrocarbon receptor (AhR) or estrogen receptor (ER), and epigenetic silencing. Together, genotoxic and nongenotoxic mechanisms can alter signal-transduction pathways, finally resulting in hypermutability, genomic instability, loss of proliferation control, and resistance to apoptosis—features characteristic of cancer cells. At early stages of tumorigenesis the nongenotoxic effects are reversible and may require continuous presence of the compound. Long-term exposure to low doses of genotoxic carcinogens also contributes to nongenotoxic alterations. Some nongenotoxic environmental carcinogens weaken cell-cycle checkpoint functions, thus leading to genetic instability or to heritable alterations of the genome.219,295

NONMALEFICENCE The ethical principle of causing no harm. See also precautionary principle.


Nonparametric methods 168

NONPARAMETRIC METHODS See distribution-free method.
NONPARAMETRIC TEST See distribution-free method.
NONPARTICIPANTS (Syn: nonresponders) Members of a study sample or population

who do not take part in the study for whatever reason, or members of a target popula- tion who do not participate in an activity. Differences between participants and non- participants have been demonstrated repeatedly in studies of many kinds, and this is often a source of bias.

NO-OBSERVED-ADVERSE-EFFECT LEVEL (NOAEL) The highest dose at which no adverse health effects are detected in an animal population. A NOAEL-SF is a no- observed-effects level with an added safety factor for human exposures; it is used in setting human safety standards. In practice, the safety factor added is commonly two or more orders of magnitude (i.e., a hundredfold or a thousandfold greater than the NOAEL).


  1. What is usual; e.g., the range into which blood pressure values usually fall in a population group, the dietary or infant feeding practices that are usual in a given culture, or the way that a given illness is usually treated in a given health care system.
  1. What is desirable; e.g., the range of blood pressures that a given authority regards as being indicative of present good health or as predisposing to future good health, the dietary or infant feeding practices that are valued in a given culture, or the health care procedures or facilities for health care that a given authority regards as desirable. In the latter sense, norms may be used as criteria in evaluating health care in order to determine the degree of conformity with what is desirable (e.g., the average length of stay of patients in hospital). Behavior that is considered culturally desirable and appropriate and therefore expected from members that belong to the community.


  1. Within the usual range of variation in a given population or group. Frequently occurring in a given population or group. In this sense, “normal” is frequently defined as “within a range extending from two standard deviations below the mean to two standard deviations above the mean,” or “between specified percentiles of the distribution” (e.g., the 10th and 90th percentiles).
  1. Indicative or predictive of good health or conducive to good health. For a diagnostic or screening test, a “normal” result is one in a range within which the probability of a specific disease is low. See also normal limits
  1. (Of a distribution) Gaussian distribution or normal distribution.

NORMAL DISTRIBUTION (Syn: Gaussian distribution) The continuous frequency distri- bution of infinite range whose probability density is given by the equation

where x is the abscissa, f(x) is the ordinate, μ is the mean, e ≈ 2.718 is the base of the natural logarithm, and σ the standard deviation. All possible values of the variable are displayed on the horizontal axis. The relative frequency (relative probability) of each value is displayed on the vertical axis, producing the graph of the normal distribution.

The properties of a normal distribution include the following:

  1. It is a continuous, symmetrical distribution; both tails extend to infinity.
  1. The arithmetic mean, mode, and median are identical.
  1. Its shape is completely determined by the mean and standard deviation.
  1. In common situations found in epidemiology, it is the approximate distribution for
    sums and means of variables provided that there are enough variables being summed or averaged, no one variable dominates the sum or average, and the variables are not too highly correlated among themselves. Then this is so even if the component variables are not themselves normal. An example is the mean of independent binary variables; the individual variables are far from normal, but the distribution of their mean gets close to normal even if there are as few as five of them. This property is sometimes called the central limit property.

NORMAL LIMITS The limits of the “normal” range of a test or measurement, in the sense of being indicative of or conducive to good health. One way to determine normal limits is to compare the values obtained when the measurements are made in two groups, one that is healthy and has been found to remain healthy and another that is ill or subse- quently found to become ill. The result may be two overlapping distributions. Outside the area where the distributions overlap, a given value clearly identifies the presence or absence of disease or some other manifestation of poor health. If a value falls into the area of overlap, the individual may belong either to the normal or the abnormal group. The choice of the normal limits depends upon the relative importance attached to the identification of individuals as healthy or unhealthy. See also false negative; false positive; sensitivity and specificity.

NORMATIVE Pertaining to the normal, usual, accepted standards or values. See also norm.

NOSOCOMIAL Relating to a hospital. Arising while a patient is in a hospital or as a result of being in a hospital. Denoting a new disorder (unrelated to the patient’s primary con- dition) associated with being in a hospital.

NOSOCOMIAL INFECTION (Syn: hospital-acquired infection) An infection originating in a medical facility; e.g., occurring in a patient in a hospital or other health care facil- ity in whom the infection was not present or incubating at the time of admission.52,57 Includes infections acquired in the hospital but appearing after discharge; it also includes such infections among staff. See also hospital epidemiology.

NOSOGRAPHY, NOSOLOGY Classification of ill persons into groups, whatever the cri- teria for their classification, and agreement as to the boundaries of the groups. The assignment of names to each disease entity in the group results in a nomenclature of disease entities, or nosography.296

NOTIFIABLE DISEASE A disease that, by statutory requirements, must be reported to the public health authority in the pertinent jurisdiction when the diagnosis is made. A disease deemed of sufficient importance to the public health to require that its occurrence be reported to health authorities.

The reporting to public health authorities of communicable diseases is, unfortunately, very incomplete. The reasons for this include diagnostic inexactitude; the desire of patients and physicians to conceal the occurrence of conditions carrying a social stigma (e.g., sexually transmitted diseases); and the indifference of physicians to the usefulness of information about such diseases as hepatitis, influenza, and measles. Yet notifications are extremely important. They provide the starting point for investigations into the failure of preventive measures, such as immunizations, for tracing sources of infection, finding common vehicles of infection, describing the geographic clustering of infection, and various other purposes, depending upon the particular disease.

n.s., n.s. Abbreviation, usually written lower case, for not statistically significant. See also significance.

NUCLEOPHILIC Having an affinity for positive charge; molecules that behave as electron donors. Nucleophilic or chemically inert compounds such as aromatic and heterocyclic amines, aminoazo dyes, polycyclic aromatic hydrocarbons (PAHs), N-nitrosamines, and others represent the great majority of human carcinogens; because these chemicals do not react directly with cellular constituents—they require enzymatic conversion into their ultimate carcinogenic forms—they are termed procarcinogens. See also elec- trophilic.

NULL HYPOTHESIS The statistical hypothesis that one variable has no association with another variable or set of variables, or that two or more population distributions do not differ from one another. In statistical terms, the null hypothesis states that the differ- ences observed in a study or test occurred as a result of the operation of chance alone. See also test hypothesis.

NULL STUDY A study that fails to find evidence for an association or effect (e.g., coffee drinking does not increase or decrease the risk of colon cancer). The term is more pre- cise than the often used synonym negative study.

NUMBER NEEDED TO HARM (NNH) (Syn: Number Needed to be treated to Harm one person)

  1. The number of persons needed to be treated, on average, to produce one more adverse event (e.g., occurrence of a disease, complication, adverse reaction, relapse). The number of persons who need to receive the treatment for one of them to experience an adverse effect. It is a clinically oriented way of expressing the risk of one intervention over another and takes the absolute risk of the event into account. It is used to summarize results of studies and to assist in clinical decision making.
  1. The reciprocal of the absolute risk increase. Let ARC be the absolute risk of events in the control group and ART the absolute risk of events in the treatment group; then the absolute risk increase (ARI) = ART – ARC and NNH = 1 / ARI. It may also be calculated as 100 divided by the ARI to express it as a percentage.14,15 Example: the occurrence of adverse outcomes in a clinical trial was 10% (0.10) in the treated group and 4% (0.04) in the placebo group; hence, the ARI was 0.06 and 1 / 0.06 = 16.7; i.e., on average, about 17 patients have to be treated in order to increase the number having an adverse outcome by 1.

Definitions 1 and 2 look equivalent but are not the same unless the treatment acts independently of other background factors leading to the harm. See also absolute risk reduction (ARR); number needed to treat (NNT); relative risk reduction (RRR).

NUMBER NEEDED TO SCREEN (NNS) The average number of persons who must undergo a screening test and the ensuing diagnostic and therapeutic procedures in order to prevent one case of the disease of interest:


where NNT is the number needed to treat and PrC is the prevalence of carriers of the variant of interest in the population screened. When the NNT is to be used to compute the NNS, computation of the NNT is based, as usual, on the reciprocal of the absolute risk reduction (ARR) (i.e., NNT = 1 / ARR); yet in genetic screening, the ARR is the lifetime risk of the disease among carriers of the genetic variant of interest minus the risk of the disease achieved once the carriers are identified, diagnosed, and treated with the available means. A reasonable (low) NNS is attained only by screening for highly penetrant genetic variants in high-risk families, not for such mutations in the general population or for low-penetrant polymorphisms.213 See also genetic penetrance; monogenic diseases; polygenic diseases; screening.

NUMBER NEEDED TO TREAT (NNT) (Syn: Number Needed to be Treated)

  1. The number of persons needed to be treated, on average, to prevent one more event (e.g., occurrence of a disease to be prevented, complication, adverse reaction, relapse). It is a clinically meaningful way of expressing the benefit of an intervention over another; it takes the absolute risk of the event into account. It is used to summarize results of studies and to assist in clinical decision making.297,298
  1. The reciprocal of the absolute risk reduction. Let ARC be the absolute risk of events in the control group and ART the absolute risk of events in the treatment group; then the absolute risk reduction (ARR) = ARC – ART and the NNT = 1 / ARR. It may also be calculated as 100 divided by the ARR expressed as a percentage. Example: the occurrence of adverse outcomes in a clinical trial was 10% (0.10) in the placebo group and 4% (0.04) in the treated group; hence the ARR was 0.06 and 1 / 0.06 = 16.7 (i.e., on average, about 17 patients have to be treated in order to prevent one of them from having an adverse outcome or to reduce the number having an adverse outcome by 1). The ARR is higher and the NNT lower in groups with higher
    absolute risks.14,15

Definitions 1 and 2 seem equivalent but are not so unless the treatment acts independently of other background factors leading to the harm. See also measure of association; number needed to harm; relative risk reduction (RRR).

NUMERATOR The upper portion of a fraction, used to calculate a rate or a ratio. See also denominator.

NUMERICAL TAXONOMY The construction of homogeneous groupings or taxa using numerical methods.